Targeting Neuroinflammation to Treat Alzheimer’s Disease

Abstract

Over the past few decades, research on Alzheimer’s disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that—upon engagement of pattern recognition receptors—induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.

FormalPara Key Points
Neuroinflammation plays an important part in the pathogenesis of Alzheimer’s disease (AD), with both positive and negative consequences.
Induction of inflammatory signaling pathways leads to the production and release of immune mediators, which ultimately compromises neuronal function and causes cell death.
Anti-inflammatory therapeutic approaches to modify AD progression are the basis for ongoing and future therapeutic trials in this area.

Introduction

Dementias and related diseases of cognitive decline pose an enormous and growing disease burden on our societies and health economies. According to the most recent World Health Organization (WHO) global disease burden report [1], deaths from neurological diseases have risen by 114% over the past 20 years to 1.2 million in 2010. The increase is largely driven by neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease and by an aging population in general. Not surprisingly, the development of strategies to curb this frightening surge is a high priority for life science research. The responsible allocation of these resources requires the identification of valid therapeutic targets. The immune system is particularly alluring in this regard.

How the immune system and peripheral infections contribute to cognitive decline remains incompletely understood, but the past 15 years have established a key role for inflammation in the progression of age-related neurodegeneration. The immune privilege of the brain is clearly not absolute, and cells of the central nervous system (CNS) are sensitive to inflammatory events occurring both within and outside of the brain.

We summarize the current state of neuroinflammation research from cellular to molecular mechanisms, as they pertain to the pathogenesis of AD. Further, we outline leverage points for preventive strategies and therapeutic approaches to stem the daunting surge in dementia diseases facing our society.

Cellular Players

Microglia

Microglia are the principal innate immune cells in the brain, and they are often considered the macrophages of the CNS. Recent studies have shed light on their origin from erythromyeloid progenitors from the yolk sac [2, 3], which migrate into the brain at embryonic day 7.5 where they further differentiate into microglial cells [2]. Microglia exhibit the capacity of self-renewal within the brain [4, 5], likely arising from a newly identified progenitor [6]. Microglia continuously survey their microenvironment and monitor ongoing synaptic activity, including synapse remodeling, debris clearance, and trophic support for neurons. In addition, they drive a major part of the innate immune response. Microglia react to pathological triggers via pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) [7,8,9].

Microglia are also phagocytic cells and can ingest amyloid β (Aβ) through a range of cell surface receptors, including cluster of differentiation (CD)-14, toll-like receptor (TLR)-2, TLR4, α6β1 integrin, CD47, and scavenger receptors, such as CD36 [10,11,12,13]. It has been suggested that, in AD, a key factor in the accumulation of Aβ throughout the brain is the failure of microglia to remove extracellular amyloid [14,15,16]. Indeed, in cortical tissue specimens from patients with AD, the microglia surrounding plaques are impaired at Aβ uptake [15, 17, 18]. Newly developed positron emission tomography (PET) techniques employ radio ligands to detect activated microglia in vivo [19,20,21]. Many tracers target the 18 kDa translocator protein (TSPO) [19], an outer mitochondrial membrane protein present in microglia, which is upregulated during activation [22,23,24]. The 11C-PK11195 ligand was the first prototypical TSPO ligand, although second-generation tracers have been developed more recently with improved signal-to-noise ratios [25]. However, a common polymorphism significantly influences the binding affinity of these new compounds [26], thus making genetic screening a necessary step for accurate quantification [27]. TSPO upregulation has been described in prodromal AD and in manifest AD dementia, using both 11C-PK11195 [28,29,30,31] and second-generation tracers [32,33,34,35,36] in regions known to be affected by AD pathology and beyond. Mixed evidence has emerged regarding the relationship between in vivo microglial activation and Aβ plaque burden [29, 31, 32, 37, 38].

Astrocytes

Under pathological conditions, astrocytes exhibit morphological changes, including hypertrophy and upregulation of glial fibrillary acidic protein (GFAP). Astrocytes can detect aggregated proteins such as Aβ or respond to inflammatory molecules (e.g., cytokines, chemokines, see below). Indeed, significant astrocyte reactivity has been reported in sporadic [39,40,41] and familial AD [42]. Similar to microglia, reactive astrocytes can polarize their processes around amyloid plaques and are capable of amyloid plaque degradation [43, 44]. Altered calcium signaling [45], impaired glutamate homeostasis [46, 47], and increased production of inflammatory mediators by astrocytes are also observed in AD.

Oligodendrocytes

The involvement of oligodendrocytes in AD remains poorly understood, although there is emerging evidence that these cells contribute to the pathogenesis and progression of neurodegenerative disorders, including AD [48]. Bartzokis et al. [49,50,51,52] demonstrated that the loss of myelin integrity that normally occurs during aging is strongly aggravated in human presenilin-1 familial, preclinical, and sporadic AD cases, particularly near Aβ plaques. In addition, focal loss of oligodendrocytes has been observed in sporadic cases of AD. This demyelination was also found in transgenic mouse models of AD, specifically at the core of Aβ plaques [52]. Focal oligodendrocyte loss has also been detected in Tg2576 and APP/PS1 transgenic mice [52], a phenomenon that may negatively influence cortical processing and neurite formation. Several cellular processes such as neuroinflammation, oxidative stress, and/or apoptosis may contribute to oligodendrocyte dysfunction and death [52]. In addition, Aβ can impair the survival and maturation of oligodendrocyte progenitor cells and the formation of the myelin sheath [53].

Myeloid Cells Other than Microglia

In addition to microglia, a variety of other monocytic cells have been found in the brain, including perivascular cells, meningeal macrophages, choroid plexus macrophages, and peripheral blood-derived monocytes [54]. These cells may, under certain circumstances, also phagocytize and degrade amyloid plaques in a transgenic model of AD [55]. Migration of peripheral monocytes is dependent on C-C chemokine receptor type 2 (CCR2), as its ablation in Tg2576 mice results in decreased recruitment of these cells and a corresponding increase in amyloid pathology [56]. In contrast, blocking transforming growth factor (TGF)-β signaling increased peripheral myeloid cell infiltration into the CNS and significantly reduced the amyloid burden [57]. Glatiramer acetate has also been shown to increase recruitment of peripheral monocytes to the CNS, and this reduces amyloid deposition. Ablation of bone marrow-derived myeloid cells in this model exacerbated amyloid pathology [58]. In contrast, when resident microglia were ablated from the APP/PS1 and APP23 mouse models, recruitment of peripheral myeloid cells was not sufficient to clear amyloid load [59, 60]. Furthermore, a recent parabiosis experiment found no evidence of monocyte infiltration around amyloid plaques [61]. Thus, the extent of myeloid infiltration into the brain and its contribution to damage or clearance of pathological proteins is still not fully understood. A particularly critical aspect of this body of work is the complexity and toxicity of experimental approaches used.

PAMPs and DAMPs: Inducers and Modulators of Neuroinflammation in Alzheimer’s Disease

During periods of pathogen invasion or tissue damage, DAMPs and PAMPs alert the immune system of the host and trigger an appropriate response to the insult.

DAMPs encompass a diverse class of molecules. A well-characterized group of DAMPs consists of intracellular proteins that are expressed at a basal level within a cell and are released after injury. These include high-mobility group protein B1 (HMGB1), S100 proteins, heat shock proteins (HSPs), chromogranin A, and Aβ. A second class of DAMPs comprises nucleic acids and nucleotide derivatives, such as mitochondrial DNA (mt-DNA), DNA, and adenosine triphosphate (ATP) [62]. In contrast, PAMPs mainly include microbial molecules that are normally not present in human cells, such as lipid A, flagellin, lipoproteins from Gram-positive and Gram-negative bacteria, bacterial DNA containing particular CpG motifs, and fragments of bacterial peptidoglycan [63].

Both PAMPs and DAMPs contribute to neuroinflammation in AD. Aβ can induce inflammatory responses [64] via activation of pattern recognition receptors (PRRs) of the innate immune system, including TLR2 [65], TLR4, and TLR6, as well as their co-receptors, CD36, CD14, and CD47. Neutralization by CD14 antibodies can reduce the Aβ-induced microglial activation [66]. Furthermore, the NLRP1 and NLRP3 inflammasome can sense a range of aggregated proteins, including Aβ [67]. Indeed, lack of NLRP3 and caspase-1 has been shown to protect mice from AD pathology [67, 68].

HMGB1 levels are increased in AD brains and are associated with senile plaques, promoting their stabilization [69]. It has been shown that microglia stimulation by HMGB1 can reduce Aβ phagocytosis [69]. HMGB1 promotes the migration and proliferation of immune cells through binding to advanced glycation end-product receptors (RAGE) and TLRs [70]. HMGB1 can also act in concert with other factors such as chemokines, growth factors, and PAMPs, together promoting immune system activation [71, 72].

Chromogranin A is associated with microglial activation in neurodegeneration [73, 74] and induces the release of interleukin (IL)-1β, indicating that TLRs and the NLRP3 inflammasome are involved in this pathway [75]. In AD, increased levels of chromogranin A have been observed in senile plaque dystrophic neurites [76]. Interestingly, the immune stimulatory potential appears almost identical to bacterial lipopolysaccharide (LPS), at least in vitro [77].

Many S100 proteins are involved in AD, including S100A9, S100A8, and S100B. S100A8 and S100A9 form a complex that is increased in the brain and cerebrospinal fluid (CSF) of patients with AD [78, 79] and can activate microglia through TLR4. Furthermore, S100A8-mediated inflammatory stimuli are connected with the upregulation of the β-site β-amyloid precursor protein (APP)-cleaving enzyme BACE1, which is involved in APP processing [80, 81]. S100B has been observed in both Aβ plaques and in the CSF [82, 83], and overexpression of human S100B exacerbates amyloidosis and gliosis in the Tg2576 AD mouse model [84].

Likewise, mt-DNA and DNA can be released from the cells and act as DAMPs upon entering the blood circulation, causing inflammation [85]. mt-DNA can bind to TLR-9 and mediate the release of tumor necrosis factor (TNF)-α and type I interferons (IFNs) [86]. Moreover, cell free DNA can bind to TLR and non-TLR receptors. Upon TLR binding, DNA activates the nuclear factor (NF)-κB pathway, thereby promoting pro-inflammatory cytokine production [87]. DNA can also bind to the absent in melanoma 2 (AIM2) inflammasome, releasing IL-1β, through the caspase-1 activation pathway.

HSPs bind to several receptors, such as TLR2 and TLR4, resulting in the production of inflammatory cytokines, such as TNFα and IL-1β [88,89,90]. Furthermore, HSPs may also exert beneficial effects in AD, thus, HSP70 can bind to APP and reduce the secretion of Aβ1-40 and Aβ1-42 through interference with the APP processing pathway [91]. HSP70, together with HSP90, can also interact with tau and Aβ oligomers and degrade them by employing proteasomal degradation [92].

Endogenous Modulators

Neurotransmitters such as ATP, glutamate, dopamine, and various neurotrophic factors, e.g., brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), can act as endogenous modulators. Microglial cells are equipped with a plethora of neurotransmitter receptors, which makes them a primary target, particularly as sites of non-synaptic release [93]. In AD, ATP production from neurons declines. Mitochondrial dysfunction, as evidenced by reduced ATP, is related to oxidative stress in AD pathology [94]. Oxidative stress can also initiate inflammatory responses and contributes to the etiopathology of AD [95].

In AD, glutamatergic neurotransmission is disturbed because of an increased amount of soluble Aβ oligomers [96]. The possible inflammatory process occurs subsequently through activation of microglia with TNFα release, synergizing with N-methyl-d-aspartate (NMDA)-mediated neurodegeneration [97]. However, the modulation of glutamate can be either pro- or anti-inflammatory depending on the expression of different groups of glutamate receptors (GluRs) on microglia and, most likely, on astroglial uptake capabilities [98, 99].

Dopamine possibly mediates the activation of microglia by triggering the mitogen-activated protein kinase (MAPK)–NFκB cascade and inducing toxicity versus dopaminergic neurons [100, 101]. In general, acetylcholine prevents the inflammatory response in microglia via α7-nicotinic acetylcholine receptors, mediated by the PLC/IP3/Ca2+ signaling pathway [102]. In patients with AD, significant loss of cholinergic neurons is tightly related to the progression of the disease. Failure in cholinergic neurotransmission decreases the cholinergic input to microglia, which in turn results in microglial activation [103]. In addition, stimulation of microglia with norepinephrine suppressed inflammation through cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling cascades [104, 105]. Of note, the locus ceruleus, the chief source of noradrenaline (NA) in the human brain, degenerates very early in the disease course. Thus, its projection regions, most prominently the limbic system and neocortex, experience decreased levels of NA. Modeling this in rodents increased Aβ-induced inflammation [106, 107] and substantially increased neuronal death and memory deficits [108]. Using 2-photon laser microscopy, it was demonstrated that depletion of NA in APP/PS1 transgenic mice caused complete inhibition of microglial Aβ clearance, and, subsequently, an increase in the number and volume of Aβ deposits [104]. The replenishment of NA levels in the cortex and hippocampal after treatment with l-threo-DOPS, an NA precursor, partly rescued this phenotype.

The levels of BDNF and NGF are severely altered in the brains of patients with AD. BDNF is released by activated microglia and inhibits the release of TNF-α and IFN-γ, whereas it promotes the expression of anti-inflammatory cytokines IL-4, IL-10, and IL-11 [109]. However, an in vitro study has also shown prolonged microglial activation through a positive feedback loop by autocrine BDNF [110], demonstrating that BDNF may modulate inflammation at various levels. In addition, evidence from a human microglial cell line suggested that NGF synthesis is potentially stimulated by inflammatory signals (cytokines and complement factors), as well as by exposure to Aβ25-35, through NFκB-dependent and -independent mechanisms.

Inflammatory Mediators

Cytokines

Cytokines are released by glial cells, such as astrocytes and microglia, upon every inflammatory challenge [111,112,113]. Many cytokines, such as IL-1β and IL-12, have been related to the progression of AD pathology [114, 115]. Increased IL-1β serum levels have been linked to AD and patients with mild cognitive impairment, a putative prodromal phase of dementia [114, 116]. Several studies have reported associations between IL-1β polymorphisms and the onset of AD pathology [115, 117, 118], linking both IL-1β polymorphisms and apolipoprotein E (APOE)-ε4 to higher levels of IL-1β in the blood and sleep disturbance in patients [119]. IL-12 is related to the regulation of the adaptive and the innate immune system [120], and an IL-12 polymorphism has been linked to AD in a Han Chinese population [121]. Vom Berg et al. [122] suggested that inhibition of the IL-12/IL-23 pathway may attenuate AD pathology and cognitive deficits due to a decrease in the IL-12p40 subunit and its receptor activity [122]. In this study, the concentration of IL-12p40 was increased in the CSF of patients with AD. Regarding anti-inflammatory cytokines, IL-10 deletion attenuated AD-related deficits, such as altered synaptic integrity and behavioral deficits in APP/PS1 mice [123]. Chakrabarty et al. [124] showed that the overexpression of IL-10 using adeno-associated viruses (AAVs) increased amyloid deposition, behavioral deficits, and synaptic alterations and impaired microglial phagocytosis of Aβ in the APP transgenic mouse model [124].

Another major regulator of inflammation is TGF-β. Increased TGF-β has been observed in amyloid plaques [125] and in the CSF of patients with AD [126, 127]. However, this cytokine plays a dual role in AD. Overexpression of TGF-β in vivo induces Aβ deposition in cerebral blood vessels, but it may also decrease microgliosis while increasing Aβ phagocytosis [128]. A link between TGF-β and neuro-fibrillary tangles (NFTs) has also been reported [129].

Chemokines

Chemokines participate in the chemoattraction of immune cells from the periphery to the brain and in the recruitment and activation of resident glial cells. In AD, chemokines are implicated in both the resolution and the propagation of pathology [130]. The most intensively studied chemokines in AD are CX3C chemokine ligand 1 (CX3CL1) and chemokine ligand 2 (CCL2).

CX3CL1, also termed fractalkine, is expressed by neurons, whereas its receptor, CX3CR1, is predominantly expressed by microglia [131, 132]. The participation of this chemokine in the pathophysiology of AD is complex since CX3CL1/CX3CR1 signaling can have a beneficial role in the context of tau pathology [132,133,135] or a detrimental role in an amyloid context [136]. In fact, in an amyloid model, deficiency of CX3CR1 decreased Aβ deposition [136] but worsened tau pathology and lowered cognitive performance [133, 134]. Moreover, the expression of CX3CL1 has been shown to be increased in tau-injured neurons but decreased in the brains of APP transgenic mice [137]. However, in human patients, the level of CX3CL1 is inversely correlated with AD severity [138]. Together, this may point to the possibility that the same inflammatory mediator may adopt various, if not opposing, effects and properties during disease progression.

CCL2 has also been associated with a dominant role in chronic inflammation [139]. A recent study has demonstrated that the CCL2/CCR2 pathway of astrocyte-induced microglial activation is associated with “M1-polarised” and enhanced microglial activity [140]. In AD, CCL2 levels were increased in mild but not in severe AD, suggesting that elevated CCL2 may play a pathogenic role during early AD stages [141]. In agreement with this, Westin et al. [142] showed that CCL2 is associated with a faster cognitive decline in early disease stages. Kiyota et al. [143] found accelerated neurodegeneration in APP/CCL2 transgenic mice, indirectly suggesting that direct inhibition of CCL2 signaling may modify microglial activation, resulting in lower Aβ deposition and improving behavioral outcomes. CCL2 overexpression accelerated oligomeric and diffuse Aβ deposition and led to spatial and working memory deficits by affecting Aβ seeding in Tg2576 mice [143].

Other Mediators

Nitric oxide (NO) is synthesized by three different isoforms of NO synthase (NOS). Each isoform plays a role in either AD progression or prevention, suggesting that NO can be neuroprotective or neurotoxic. High doses of LPS induced robust CNS inflammation and microglia-induced release of NO. NO in the CNS can influence many signaling pathways, including protein nitrosylation, impairment of long-term potentiation, or inhibition of mitochondrial respiration. The impact of NO signaling depends on the local cellular environment. In the AD brain, NO mainly derives from the inducible isoform of NOS, NOS2, which is expressed by neurons [144], microglia, and astrocytes [145]. Nitrosative stress has been shown to affect all types of cellular proteins, including, but not restricted to, synaptic proteins. Post-translational protein modification can take place either by s-nitrosylation of cysteine residues or by nitration of tyrosine residues. Importantly, Aβ itself represents a nitration target at tyrosine 10 of its amino acid sequence. Nitration at this position strongly increases the peptide’s propensity to aggregate, and nitrated Aβ predominantly resides in the core of the deposits, suggesting that this mechanism contributes to the initiation of deposition [146].

Effect of Neuroinflammation on Neuronal Function

Cytokines and Synaptic Scaling

Synaptic plasticity is strongly influenced by basal levels of cytokines [147]. Emblematic is the case of “synaptic scaling,” a well-defined form of homeostatic plasticity that regulates the density of GluRs at presynaptic and postsynaptic sites [148]. A homeostatic reduction of neuronal excitability by withdrawal of GluRs is termed down-scaling, whereas the increase of neuronal excitability (by accumulation of GluRs) is known as up-scaling. TNFα has been shown to support synaptic up-scaling by increasing AMPA receptor-dependent miniature excitatory postsynaptic currents (mEPSC). Importantly, TNFα required for up-scaling synapses is derived from glial cells [149] and not from neurons themselves. Such evidence implies that glial cells are able to release cytokines in response to changes in neuronal activity. By contrast, enhanced release of inflammatory cytokines, for instance during chronic peripheral inflammation, can disrupt the physiological mechanisms of synaptic plasticity, promoting neuronal hyper-excitability and increased susceptibility to seizure generation [150].

A growing body of evidence demonstrates that microglia can actively respond to increased neuronal excitability, and microglial processes make physical contact with excitatory synapses [151,152,153,154]. This type of microglia–synapse interaction has been shown to reduce neuronal excitability [110, 155], potentially as a form of a regulatory mechanism for preventing glutamatergic excitotoxicity [152].

Microglia and Synaptic Pruning

Microglia can actively participate in remodeling synaptic connections (“synaptic pruning”). A pathological form of synaptic pruning may represent a commonly shared mechanism among several neurological conditions of different nature: a recent study in a murine model of chronic stress, showed electron-dense (dark) microglia co-localized with synaptic terminals. This microglial phenotype associated with synaptic pruning appeared clearly reactive, possibly accounting for an increased loss of synapses during chronic inflammation [156]. Microglia may also remove synapses in a complement-dependent manner in a mouse model of West Nile virus-induced neuroinflammation [157]. Mice with either a deficit in the number of microglia (IL-34−/−) or a deficiency of complement components (such as C3 protein or complement receptor 3 knock-out) were protected from inflammation-induced synaptic loss [157].

An alternative hypothesis suggests that pathological pruning of synapses during inflammation may also represent a form of “tissue remodeling” for auto-protective purposes [158]. A study suggested that upon LPS injection, microglia pruned preferentially GABAergic terminals, thereby increasing excitatory synaptic activity and induction of neurotrophic pathways in downstream neurons. This mechanism has been interpreted as an attempt to promote neuronal viability in a pathological context, although the price was a temporary imbalance of synaptic connectivity [159].

In mouse models of Aβ deposition, complement protein C1q was elevated as early as 1 month of age in both DG and frontal cortex. At this timepoint, neither plaques nor synaptic loss are detectable. At a later age (mice aged 3–4 months), the number of synapses decreased significantly; however, synaptic loss was rescued almost completely in the absence of either C1q, C3, or CR3. Additionally, intracerebroventricular (ICV) injection of oligomeric Aβ in wild-type mice induced synapse loss and activated a phagocytic phenotype in microglia. Moreover, synapse loss in response to oligomeric Aβ was not observed in C1q or CR3 knock-out mice [160] (Table 1).

Table 1 Randomized clinical trials of non-steroidal anti-inflammatory drugs in patients with Alzheimer’s disease

Similar findings have been obtained in a mouse model deficient for the progranulin gene, typically associated with frontotemporal dementia (FTD) in humans [161, 162]. Lack of progranulin has been shown to trigger an exaggerated inflammatory reaction in microglia and macrophages [161, 163]. Interestingly, the brains of progranulin-deficient mice showed increased levels of complement proteins, a prominent pro-phagocytic activation of microglia, and enhanced pruning of synapses [164].

Inflammation and Neurogenesis

Under homeostasis, immunological signals can actively shape adult neurogenesis. Microglia were shown to rapidly engulf and remove apoptotic neuronal progenitors, remarkably, without any trace of inflammatory reaction [165, 166]. Other evidence has pinpointed a close interplay between different immune proteins and the neurogenic process [167, 168]. IL-1β has often received particular attention because of its anti-neurogenic activity [169,170,171,172,173,174,175]. One may assume that microglia are primarily responsible for this reduction of neurogenesis during inflammatory challenges. An interesting molecular player is the CX3C axis between neurons and microglia, which is known to preserve the microglial “resting” phenotype under physiological conditions [176, 177]. Several consistent findings showed reduced neurogenesis in CX3CR1-deficient mice, along with increased NF-κB activation and IL-1β expression in microglia [178,179,180,181]. Consistently, when an inflammatory challenge is applied under CX3CR1-deficient conditions, microglia release an increased and uncontrolled amount of inflammatory mediators and free radicals, causing neurotoxicity and cognitive/behavioral deficits [132, 182]. Interestingly, during ageing, neurons decrease expression of CX3CL1 [183], which likely would result in a general downregulation of the CX3C axis and pro-inflammatory skewing of microglia [184, 185]. Pro-inflammatory microglial priming has been suggested as a possible mechanism leading to the dysregulated microglial function and the ensuing stepwise decline of neurogenesis (and potentially neurodegeneration) during senility [186,187,188,189,190,191,192]. In contrast, several lines of evidence point towards the pro-neurogenic function of microglia, especially during the period of early brain development. These indications suggest that microglia play an important role during brain development, axonal guidance, and formation of neuronal networks.

Astrocytes and Glutamate Reuptake

In the CNS, extracellular levels of glutamate are tightly regulated by astrocytes in order to modulate GluR activity and prevent potential excitotoxicity [193]. Once in the synaptic cleft, excess glutamate is promptly scavenged by the excitatory amino acid transporters (EAATs) expressed on both neurons and astrocytes [194]. The astrocytic EAAT2 is thought to be responsible for about 90% of all glutamate uptake in the brain [195, 196]. There are no synaptic enzymes that otherwise would degrade glutamate. Therefore, astrocyte-mediated glutamate uptake represents the primary mechanism for the homeostatic regulation of glutamate bioavailability [197]. Impairment of glutamate uptake causes excitotoxicity characterized by overload of cellular calcium, generation of free radicals, and protein/lipid oxidation. Notably, astrocyte glutamate transporters (EAAT1 and EAAT2) were shown to be reduced in the cortex and hippocampus of patients with AD [46, 198]. Moreover, Aβ-induced neurotoxicity in vivo has been associated with NMDA receptor-dependent excitotoxicity [199]. In conclusion, pharmaceutical compounds aiming to modulate glutamate excitotoxicity have revealed a certain therapeutic potential for neurodegenerative diseases (Table 2).

Table 2 Clinical trials of non-non-steroidal anti-inflammatory drugs in patients with Alzheimer’s disease

Function and Dysfunction of the Blood–Brain Barrier

Dysfunction of the blood–brain barrier (BBB) is a relatively new frontier in AD research [200,201,202]. The fully functional BBB is a highly specialized monolayer of endothelial cells lining the cerebrovasculature and separating the circulating blood from the brain parenchyma. The integrity of the BBB depends critically on the functional state of the associated pericytes, astrocytes, and microglia and is compromised during neuroinflammation [203]. Aβ binds to low-density lipoprotein receptor-related protein-1 (LPR1) on the endothelial cells of the brain capillaries and is then released into the bloodstream [204, 205]. Vice versa, in the BBB, RAGE are upregulated with aging and facilitate the influx of Aβ from the blood into the brain [206]. Deficient Aβ clearance from the brain parenchyma is thus proposed to be, at least in part, the result of its faulty transport across the BBB [207,208,209].

Modifiable Risk Factors for AD

A plethora of exogenous factors exert both beneficial and detrimental modulating effects on the inflammatory state of an organism. This, in turn, has direct and important consequences for the risk of developing AD. As these factors are amenable to non-pharmacological interventions and can be mitigated (or promoted) by preventive measures or lifestyle choices, they deserve special attention.

Infections

The evidence pointing to infections as risk factors for AD stems from epidemiological and neuropathological studies. Prospective cohort studies show that infection represents an important risk factor in the progression of dementia and AD [210, 211]. A case–control study suggested that multiple infections double the risk of developing dementia [212]. In studies of a large AD patient cohort, peripheral infection was associated with accelerated cognitive decline [213, 214]. Conversely, the frequency of various infections, including urinary and respiratory tract infections is higher among individuals with AD than among healthy, age-matched controls [215]. Indeed, pneumonia is one of the most common causes of death in AD [204, 205, 216218]. In contrast, vaccination against influenza and other infectious conditions is associated with a significantly lower risk of developing AD [219, 220].

A number of specific viral, bacterial, and fungal infections has been detected by polymerase chain reaction (PCR) in human AD brain tissue and have been implicated in AD development. One example is herpes simplex virus type 1 (HSV-1) [221,222,223], which is an AD risk factor in people carrying the APOE4 allele [224, 225]. Chlamydia pneumonia, a Gram-negative bacteria, has been detected via PCR in the brain tissue of patients with AD [226, 227], where it was found to have infected microglia, astrocytes, and neurons [227]. Interestingly, fungal proteins and DNA have been identified in the brain tissue and CSF of patients with AD [228, 229]. In postmortem AD brains, co-infection with many fungi has also been reported, with fungal material identified inside neuronal cells and in many regions [230, 231]. The significance of these findings remains uncertain because several factors, including postmortem time and handling, must be considered before conclusions are drawn. In addition, causality is notoriously difficult to ascertain in these scenarios. Systemic inflammation certainly has an impact on the brain, which is not at all “immune privileged,” as textbooks still suggest. Thus, higher rates of cognitive decline have been observed in patients with AD with acute systemic inflammation [214]. Leaky gut may be one of the drivers of systemic inflammation and is directly related to an imbalance of gut microbiota [232].

Traumatic Brain Injury

Traumatic brain injury (TBI) leads to damaged blood vessels, axons, nerve cells, and glia of the brain in a focal, multifocal, or diffuse pattern, resulting in impaired brain function [233, 234]. A single moderate or severe TBI may increase the risk of developing late-onset AD, whereas repetitive mild TBI (e.g., through contact sport) is associated with an elevated risk of chronic traumatic encephalopathy [235, 236]. Two key meta-analyses of case–control studies found a significant association between moderate-severe TBI and AD [237, 238]. Furthermore, human pathological studies evince abnormal accumulation of AD-related pathological proteins, including soluble and insoluble Aβ and hyperphosphorylated tau aggregates, following TBI. This, in turn, is supported by studies in large animals [239, 240]. Aggregation and deposition of Aβ is accelerated after an acute TBI event, with changes within a mere 24 h up to 2 months after injury in animal studies [240,241,242,243,244]. Further, aggregation and deposition of Aβ have been associated with memory impairments in 3xTg-AD mice [244]. Aberrant tau phosphorylation has also been described in several models after TBI [245,246,247,248]. The formation of misfolded Aβ and tau oligomeric seeds triggered by TBI may lead to spreading of the pathology in a prion-like manner, causing a faster and more severe onset of the disease [249].

Smoking

The role of smoking as a modifiable risk factor in AD is controversial. Some early case–control studies reported smoking had a beneficial effect on AD [250, 251]. In contrast, more recent cohort studies without affiliation to the tobacco industry clearly point towards a deleterious impact [252, 253]. Meta-analyses of these studies showed that smoking during a lifetime is associated with at least a 1.7 times higher risk of AD [254]. Although this increase obviously correlates with smoking intensity and duration [255], the findings regarding former smoking status are more heterogeneous. Reitz et al. [252] observed no association between past smoking and AD, whereas Aggarwal et al. [253] reported a lower risk for former smokers carrying the ApoEε4 allele than for those who never smoked.

It is estimated that, today, smoking accounts for 4.7 million AD cases worldwide [256]. Evidence from various in vitro and in vivo studies suggests that sustained cigarette smoke exposure facilitates the emergence of regional Aβ and tau pathology [257, 258]. Several possible pathways are likely to contribute to the development of pathological AD features in smokers. These include cerebrovascular dysfunction [259], neuroinflammation [258], and protein misfolding and aggregation [260, 261], which all may be triggered by an increase in oxidative stress [262,263,264]. However, human postmortem studies yielded contradictory results concerning the link between smoking and AD neuropathology, as Aβ levels were reduced in the brains of active smoker AD cases compared with never-smoking patients [265]. Remarkably, nicotine and some related compounds exert neuroprotective effects in a variety of model systems [266,267,268], for example via activation of nicotinic acetylcholine receptors [269] or direct binding to Aβ fibrils [270].

Physical Activity

A case–control study showed patients with AD were less active in midlife [271]. Physical inactivity is accompanied by several secondary effects, including obesity, metabolic syndrome, type 2 diabetes mellitus (T2DM), and cardiovascular disease [272]. In contrast, regular physical exercise positively influences neurogenesis, brain plasticity, and metabolic function, reduces levels of pro-inflammatory cytokines and oxidative stress [273,274,275], and can alter disease-related biomarkers in patients with dementia [276]. Thus, it is not surprising that cognitive function and mental processing speed in elderly people could be significantly improved with leisure time activities and exercise programs [256, 277,278,279]. However, Küster et al. [280] showed that a (self-reported) active lifestyle rather than the exercise itself is associated with a decreased risk of AD. Whether physical exercise benefits all patient populations equally remains controversial [276, 281]. Some studies report a stronger effect of physical activity among APOE4 carriers compared with non-carriers [282,283,284], whereas others could not replicate these results [285,286,287]. Analysis of different animal models suggests positive effects of physical exercise on BDNF levels, oxidative stress and even Aβ and tau pathology, resulting in delayed disease onset and progression [288291].

Diet and Obesity

Many specific dietary components have been studied in relation to AD. In clinical studies, a higher intake of unsaturated fatty acids, antioxidants, and vitamins B12 and folate have been associated with a lower risk for AD and cognitive decline [292,293,294]. However, the opposite or even no effect has also been found for these factors [295,296,297]. Instead of focusing on individual dietary components, the effect of overall dietary patterns (which incorporates nutrient interaction) has been examined, including the Mediterranean Diet (MeDi) [298], Dietary Approaches to Stop Hypertension (DASH) [299], and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) [300]. These studies point towards diet as having a protective effect against cognitive decline and development of AD [299, 301,302,303,304,305,306,307].

In contrast, overnutrition can lead to obesity, which in turn has been associated with AD development. Obesity is characterized by leptin and insulin resistance, leading to impaired energy metabolism and chronic inflammation [308]. This chronic inflammatory status can cause cellular stress and neurodegeneration and is thought to be the link between obesity and its adverse effects on cognitive performance and AD development [309,310,311,312,313]. Most importantly, some of these effects may occur as early as midlife. Thus, increased body mass index and sagittal abdominal diameter in men aged 40–45 years has been associated with an increased risk of AD in later life [314].

Lifetime Distress

Lifetime frequency of stress exposure is consistently associated with the incidence of mild cognitive impairment (MCI) and may increase the risk of late-onset AD [315,316,317]. In particular, higher levels of the stress hormone cortisol are associated with an accelerated age-related decline in cognition [318, 319]. The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of cortisol in humans or the corresponding corticosterone in rodents. This system is dysregulated in patients with AD, with higher cortisol levels found in the blood plasma and CSF of subjects with AD than in age-matched controls [318, 320].

Interestingly, exposing rodents to stressful experiences increases corticosterone levels and glucocorticoid receptor activation, resulting in aggravation of AD-related neuropathology in various transgenic models [321,322,323,324,325,326]. Microglia are highly responsive to glucocorticoids, with abundant glucocorticoid receptor expression levels [327]. Furthermore, glucocorticoids can induce a pro-inflammatory microglial phenotype upon stress, especially following a secondary inflammatory challenge [328,329,330].

Diabetes Mellitus

T2DM affects approximately 370 million people worldwide, accounting for 90–95% of all patients with diabetes [331]. The disease is characterized by hyperglycemia, insulin resistance, and relative lack of insulin [332]. People with T2DM have a 73% greater risk of developing dementia [333] and decreased white and grey matter volume of the temporal and frontal lobes [334, 335]. Cortical and hippocampal atrophies have also been observed in diabetic mice (db/db) [336].

Importantly, insulin resistance leads to the generation of NFTs: decreased activation of protein kinase B in T2DM results in ineffective inhibition of glycogen synthase kinase 3, thus mediating tau phosphorylation and formation of NFTs [337, 338]. In addition, insulin levels in patients with diabetes mean the insulin-degrading enzyme is sequestered away from Aβ, which fosters the accumulation of Aβ in the brain [339, 340]. Patients with T2DM have impaired immunological defense mechanisms, resulting in frequent infections, which may contribute to the development of AD [341]. The concentration of pro-inflammatory cytokines in the CSF is increased in patients with T2DM [342]; indeed, chronic sub-acute inflammation can also induce insulin resistance and cause T2DM [343].

Protection by Anti-inflammatory Strategies

Past and Present Strategies

Various anti-inflammatory therapeutic approaches have been taken to modify AD progression over the past 2 decades, ranging from non-steroidal anti-inflammatory drugs (NSAIDs) to TNFα inhibition.

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

One of those approaches was ADAPT (Alzheimer’s Disease Anti-inflammatory Prevention Trial). This trial was constructed to examine whether NSAIDs could prevent or delay the onset of AD and whether such treatment could impact cognitive decline associated with aging [344].

Early epidemiological studies had suggested that long-term treatment with NSAIDs decreased the risk of AD development [345,346,347,348]. Additionally, strong experimental evidence has emerged supporting the positive effect of NSAIDs in AD animal models [80, 349]. NSAIDs have been shown to reduce Aβ secretion and accumulation, both in vitro and in vivo, to modulate γ-secretase activity, to exert an anti-inflammatory effect, and to improve cognitive function in AD mouse models [350,351,352,353,354,355].

However, most NSAIDs have not convincingly shown any beneficial effects during clinical trials in patients with AD [356]. Only a small, early study using indomethacin in patients with AD [357], which has not been replicated, and a follow-up analysis from the ADAPT research group using naproxen [358] have shown positive effects. Aspirin also did not prove effective against AD but increased the risk of serious bleeds (AD2000 trial).

Non-NSAIDs

Peroxisome proliferator-activated receptor (PPAR)-γ agonism has consistently been shown to reduce the production of inflammatory cytokines and amyloid accumulation in AD mouse models [351, 359,360,361,362]. Rosiglitazone induces activation of the ERK pathway, leading to cognitive enhancement in AD models [363,364,365,366]. Pioglitazone has been found to improve cognition and cerebral blood flow in mild AD [367]. Additionally, pioglitazone treatment reduced dementia risk in patients with initially non-insulin-dependent diabetes mellitus in a case–control study [368]. However, a pilot randomized clinical trial for the safety of this drug in patients with AD found no significant effect [369]. Rosiglitazone has been found to delay cognitive decline in patients with early AD and MCI [370]. Another study showed improvement in cognitive function using pioglitazone, which was restricted to APOEε4 non-carriers [371]. The TOMORRW study is ongoing and will evaluate the efficacy of pioglitazone versus placebo in delaying the onset of MCI-AD in cognitively normal participants who are at high risk for developing MCI within the next 5 years (NCT01931566).

Tumor Necrosis Factor-α Inhibitors

Inhibiting TNFα signaling has also become an interesting and promising approach to the treatment of AD. A clinical case report found that intrathecal administration of infliximab (an antibody against TNFα already approved for other indications) reduced Aβ plaques and tau pathology in APP/PS1 mice and enhanced cognitive function. Additionally, two small pilot clinical studies using a different TNFα inhibitor, etanercept, showed cognitive improvement in patients with AD [372, 373]. However, these studies used small sample sizes and an open-label design and lacked a placebo group. Thus, a larger well-designed placebo-controlled study would be necessary to assess the possible utility of TNFα in AD [349].

Other Anti-inflammatory Drugs

Trials have examined other anti-inflammatory drugs, such as prednisone, hydroxychloroquine, simvastatin, and atorvastatin, but have shown no significant positive cognitive effects in patients with AD [368, 374,375,376,377,378].

Future Strategies

Recently, fenamate NSAIDs including mefenamic acid were found to selectively inhibit NLRP3 through the inhibition of volume-regulated ion channels (VRACs), thereby preventing cognitive impairments in rodent models of AD. Mefenamic acid is already on the market and is used for abdominal pain in premenstrual syndrome. MCC950, a new potent NLRP3-selective inhibitor has been developed but is not yet available for clinical use [379]. Anakinra, an IL-1 receptor antagonist, and a neutralizing antibody, canakinumab, have been proposed to work by inhibiting this NLRP3 axis, but the cost benefit and bioavailability in the brain remains a concern [380].

CSP-1103 (also known as CHF 5074 or Itanapraced) is now in phase III clinical trials as a microglia modulator. It may inhibit Aβ plaque deposition, reduce tau pathology, restore normal microglial function by increasing phagocytosis, and decrease production of pro-inflammatory cytokines [381].

Some other new therapeutic targets have been proposed. MAPKα inhibitors (e.g., Neflamapimod [VX-745]) could reduce IL-1β levels [382] (NCT02423200). Administration of low-dose IL-2 could increase plaque-associated microglia and improve cognitive performance [383]. C3aR antagonist SB290157 could decrease amyloid load and microgliosis [384]. PD-1 inhibitors could reduce plaque load and improve cognition [385]. Blocking the p40 common subunit of IL-12 and IL-23 could decrease amyloid burden [122, 359, 386]. A CD33 inhibitor might promote microglial phagocytosis of Aβ [387].

Summary and Conclusions

Neuroinflammation in AD is likely to arise from the recognition of Aβ by PRRs on the surface of innate immune cells in the brain. Once initiated, sustained inflammation and neurodegeneration may unleash further factors, which, in turn, act as DAMPs and thereby contribute to the persisting and chronic sterile immune reaction in the brain. Several mechanisms of interaction by which inflammatory processes contribute to disease progression have been identified. Given that deposition of Aβ occurs decades prior to the first amnestic and cognitive deficits, such mechanisms may represent promising therapeutic targets. Identification of suitable mode and site of intervention models, which better target the human cerebral innate immune system, and associated biomarkers, is urgently required.

References

  1. 1.

    World Health Organization. The global burden of disease: 2004 update. 2008.

  2. 2.

    Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci. 2013;16(3):273–80.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FMV. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci. 2007;10(12):1538–43.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Tay TL, Hagemeyer N, Prinz M. The force awakens: insights into the origin and formation of microglia. Curr Opin Neurobiol. 2016;39:30–7.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Elmore MRP, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014;82(2):380–97.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Baroja-Mazo A, Martín-Sánchez F, Gomez AI, Martínez CM, Amores-Iniesta J, Compan V, et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol. 2014;15(8):738–48.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci Off J Soc Neurosci. 2005;25(36):8240–9.

    CAS  Article  Google Scholar 

  9. 9.

    Sondag CM, Dhawan G, Combs CK. Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J Neuroinflamm. 2009;6:1.

    Article  CAS  Google Scholar 

  10. 10.

    Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci Off J Soc Neurosci. 2003;23(7):2665–74.

    CAS  Google Scholar 

  11. 11.

    Ries M, Sastre M. Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci (Internet). 2016;8:160. https://doi.org/10.3389/fnagi.2016.00160.

  12. 12.

    Tahara K, Kim H-D, Jin J-J, Maxwell JA, Li L, Fukuchi K. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain J Neurol. 2006;129(Pt 11):3006–19.

    Article  Google Scholar 

  13. 13.

    Wilkinson K, El Khoury J. Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer’s disease. Int J Alzheimers Dis. 2012;2012:489456.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci Off J Soc Neurosci. 2008;28(33):8354–60.

    CAS  Article  Google Scholar 

  15. 15.

    Thériault P, ElAli A, Rivest S. The dynamics of monocytes and microglia in Alzheimer’s disease. Alzheimers Res Ther. 2015;7(1):41.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16.

    Weiner HL, Frenkel D. Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol. 2006;6(5):404–16.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Frackowiak J, Wisniewski HM, Wegiel J, Merz GS, Iqbal K, Wang KC. Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol (Berl). 1992;84(3):225–33.

    CAS  Article  Google Scholar 

  18. 18.

    Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, et al. Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology. PLOS One. 2013;8(4):e60921.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Jacobs AH, Tavitian B, INMiND consortium. Noninvasive molecular imaging of neuroinflammation. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2012;32(7):1393–415.

    CAS  Article  Google Scholar 

  20. 20.

    Stefaniak J, O’Brien J. Imaging of neuroinflammation in dementia: a review. J Neurol Neurosurg Psychiatry. 2016;87(1):21–8.

    PubMed  Google Scholar 

  21. 21.

    Varley J, Brooks DJ, Edison P. Imaging neuroinflammation in Alzheimer’s disease and other dementias: recent advances and future directions. Alzheimers Dement J Alzheimers Assoc. 2015;11(9):1110–20.

    Article  Google Scholar 

  22. 22.

    Lavisse S, Guillermier M, Hérard A-S, Petit F, Delahaye M, Van Camp N, et al. Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging. J Neurosci Off J Soc Neurosci. 2012;32(32):10809–18.

    CAS  Article  Google Scholar 

  23. 23.

    Liu G-J, Middleton RJ, Hatty CR, Kam WW-Y, Chan R, Pham T, et al. The 18 kDa translocator protein, microglia and neuroinflammation. Brain Pathol Zurich Switz. 2014;24(6):631–53.

    CAS  Article  Google Scholar 

  24. 24.

    Venneti S, Lopresti BJ, Wiley CA. The peripheral benzodiazepine receptor (translocator protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol. 2006;80(6):308–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Chauveau F, Boutin H, Van Camp N, Dollé F, Tavitian B. Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging. 2008;35(12):2304–19.

    PubMed  Article  Google Scholar 

  26. 26.

    Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2012;32(1):1–5.

    CAS  Article  Google Scholar 

  27. 27.

    Turkheimer FE, Rizzo G, Bloomfield PS, Howes O, Zanotti-Fregonara P, Bertoldo A, et al. The methodology of TSPO imaging with positron emission tomography. Biochem Soc Trans. 2015;43(4):586–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In-vivo measurement of activated microglia in dementia. Lancet Lond Engl. 2001;358(9280):461–7.

    CAS  Article  Google Scholar 

  29. 29.

    Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, et al. Microglia, amyloid, and cognition in Alzheimer’s disease: an [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis. 2008;32(3):412–9.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Fan Z, Aman Y, Ahmed I, Chetelat G, Landeau B, Ray Chaudhuri K, et al. Influence of microglial activation on neuronal function in Alzheimer’s and Parkinson’s disease dementia. Alzheimers Dement J Alzheimers Assoc. 2015;11(6):608–21.e7.

    Article  Google Scholar 

  31. 31.

    Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, Bullock R, et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology. 2009;72(1):56–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Hamelin L, Lagarde J, Dorothée G, Leroy C, Labit M, Comley RA, et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain J Neurol. 2016;139(Pt 4):1252–64.

    Article  Google Scholar 

  33. 33.

    Kreisl WC, Lyoo CH, McGwier M, Snow J, Jenko KJ, Kimura N, et al. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain J Neurol. 2013;136(Pt 7):2228–38.

    Article  Google Scholar 

  34. 34.

    Suridjan I, Pollock BG, Verhoeff NPLG, Voineskos AN, Chow T, Rusjan PM, et al. In-vivo imaging of grey and white matter neuroinflammation in Alzheimer’s disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA. Mol Psychiatry. 2015;20(12):1579–87.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Varrone A, Oikonen V, Forsberg A, Joutsa J, Takano A, Solin O, et al. Positron emission tomography imaging of the 18-kDa translocator protein (TSPO) with [18F]FEMPA in Alzheimer’s disease patients and control subjects. Eur J Nucl Med Mol Imaging. 2015;42(3):438–46.

    PubMed  Article  Google Scholar 

  36. 36.

    Yasuno F, Kosaka J, Ota M, Higuchi M, Ito H, Fujimura Y, et al. Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [11C]DAA1106. Psychiatry Res. 2012;203(1):67–74.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Fan Z, Okello AA, Brooks DJ, Edison P. Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease. Brain J Neurol. 2015;138(Pt 12):3685–98.

    Article  Google Scholar 

  38. 38.

    Yokokura M, Mori N, Yagi S, Yoshikawa E, Kikuchi M, Yoshihara Y, et al. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2011;38(2):343–51.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Carter SF, Schöll M, Almkvist O, Wall A, Engler H, Långström B, et al. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med Off Publ Soc Nucl Med. 2012;53(1):37–46.

    CAS  Google Scholar 

  40. 40.

    Choo ILH, Carter SF, Schöll ML, Nordberg A. Astrocytosis measured by 11C-deprenyl PET correlates with decrease in gray matter density in the parahippocampus of prodromal Alzheimer’s patients. Eur J Nucl Med Mol Imaging. 2014;41(11):2120–6.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Santillo AF, Gambini JP, Lannfelt L, Långström B, Ulla-Marja L, Kilander L, et al. In vivo imaging of astrocytosis in Alzheimer’s disease: an 11C-L-deuteriodeprenyl and PIB PET study. Eur J Nucl Med Mol Imaging. 2011;38(12):2202–8.

    PubMed  Article  Google Scholar 

  42. 42.

    Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, Almkvist O, Farid K, Schöll M, et al. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain J Neurol. 2016;139(Pt 3):922–36.

    Article  Google Scholar 

  43. 43.

    Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang H-Y. Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003;971(2):197–209.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med. 2003;9(4):453–7.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Vincent AJ, Gasperini R, Foa L, Small DH. Astrocytes in Alzheimer’s disease: emerging roles in calcium dysregulation and synaptic plasticity. J Alzheimers Dis. 2010;22(3):699–714.

    PubMed  Article  Google Scholar 

  46. 46.

    Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L. Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol. 1996;40(5):759–66.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Scimemi A, Meabon JS, Woltjer RL, Sullivan JM, Diamond JS, Cook DG. Amyloid-β1-42 slows clearance of synaptically released glutamate by mislocalizing astrocytic GLT-1. J Neurosci Off J Soc Neurosci. 2013;33(12):5312–8.

    CAS  Article  Google Scholar 

  48. 48.

    Ettle B, Schlachetzki JCM, Winkler J. Oligodendroglia and myelin in neurodegenerative diseases: more than just bystanders? Mol Neurobiol. 2016;53(5):3046–62.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiol Aging. 2004;25(1):49–62.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Bartzokis G. Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging. 2011;32(8):1341–71.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Bartzokis G, Lu PH, Mintz J. Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer’s disease. J Alzheimers Dis. 2004;6(6 Suppl):S53–9.

    CAS  PubMed  Google Scholar 

  52. 52.

    Mitew S, Kirkcaldie MTK, Halliday GM, Shepherd CE, Vickers JC, Dickson TC. Focal demyelination in Alzheimer’s disease and transgenic mouse models. Acta Neuropathol (Berl). 2010;119(5):567–77.

    CAS  Article  Google Scholar 

  53. 53.

    Desai MK, Mastrangelo MA, Ryan DA, Sudol KL, Narrow WC, Bowers WJ. Early oligodendrocyte/myelin pathology in Alzheimer’s disease mice constitutes a novel therapeutic target. Am J Pathol. 2010;177(3):1422–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15(5):300–12.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Simard AR, Soulet D, Gowing G, Julien J-P, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron. 2006;49(4):489–502.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007;13(4):432–8.

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, et al. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med. 2008;14(6):681–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Koronyo Y, Salumbides BC, Sheyn J, Pelissier L, Li S, Ljubimov V, et al. Therapeutic effects of glatiramer acetate and grafted CD115+ monocytes in a mouse model of Alzheimer’s disease. Brain J Neurol. 2015;138(Pt 8):2399–422.

    Article  Google Scholar 

  59. 59.

    Prokop S, Miller KR, Drost N, Handrick S, Mathur V, Luo J, et al. Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease-like mice. J Exp Med. 2015;212(11):1811–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Varvel NH, Grathwohl SA, Degenhardt K, Resch C, Bosch A, Jucker M, et al. Replacement of brain-resident myeloid cells does not alter cerebral amyloid-deposition in mouse models of Alzheimer’s disease. J Exp Med. 2015;212(11):1803–9.

  61. 61.

    Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016;213(5):667–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81(1):1–5.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Vance RE, Isberg RR, Portnoy DA. Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host Microbe. 2009;6(1):10–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Inflammation in Alzheimer’s disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol. 2009;87(3):181–94.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, et al. TLR2 is a primary receptor for Alzheimer’s amyloid β peptide to trigger neuroinflammatory activation. J Immunol Baltim Md 1950. 2012;188(3):1098–107.

    CAS  Google Scholar 

  66. 66.

    Fassbender K, Walter S, Kühl S, Landmann R, Ishii K, Bertsch T, et al. The LPS receptor (CD14) links innate immunity with Alzheimer’s disease. FASEB J Off Publ Fed Am Soc Exp Biol. 2004;18(1):203–5.

    CAS  Google Scholar 

  67. 67.

    Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9(8):857–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674–8.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Takata K, Kitamura Y, Kakimura J, Shibagaki K, Tsuchiya D, Taniguchi T, et al. Role of high mobility group protein-1 (HMG1) in amyloid-beta homeostasis. Biochem Biophys Res Commun. 2003;301(3):699–703.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Degryse B, Bonaldi T, Scaffidi P, Müller S, Resnati M, Sanvito F, et al. The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol. 2001;152(6):1197–206.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Bianchi ME. HMGB1 loves company. J Leukoc Biol. 2009;86(3):573–6.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Castellani P, Balza E, Rubartelli A. Inflammation, DAMPs, tumor development, and progression: a vicious circle orchestrated by redox signaling. Antioxid Redox Signal. 2014;20(7):1086–97.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Ciesielski-Treska J, Ulrich G, Chasserot-Golaz S, Zwiller J, Revel MO, Aunis D, et al. Mechanisms underlying neuronal death induced by chromogranin A-activated microglia. J Biol Chem. 2001;276(16):13113–20.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Kingham PJ, Cuzner ML, Pocock JM. Apoptotic pathways mobilized in microglia and neurones as a consequence of chromogranin A-induced microglial activation. J Neurochem. 1999;73(2):538–47.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Terada K, Yamada J, Hayashi Y, Wu Z, Uchiyama Y, Peters C, et al. Involvement of cathepsin B in the processing and secretion of interleukin-1beta in chromogranin A-stimulated microglia. Glia. 2010;58(1):114–24.

    PubMed  Article  Google Scholar 

  76. 76.

    Weiler R, Lassmann H, Fischer P, Jellinger K, Winkler H. A high ratio of chromogranin A to synaptin/synaptophysin is a common feature of brains in Alzheimer and Pick disease. FEBS Lett. 1990;263(2):337–9.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Taupenot L, Remacle JE, Helle KB, Aunis D, Bader MF. Recombinant human chromogranin A: expression, purification and characterization of the N-terminal derived peptides. Regul Pept. 1995;56(1):71–88.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Maezawa I, Zimin PI, Wulff H, Jin L-W. Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. J Biol Chem. 2011;286(5):3693–706.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD14 and toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. J Neurosci Off J Soc Neurosci. 2009;29(38):11982–92.

    CAS  Article  Google Scholar 

  80. 80.

    Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer’s disease. Nat Immunol. 2015;16(3):229–36.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Kummer MP, Hammerschmidt T, Martinez A, Terwel D, Eichele G, Witten A, et al. Ear2 deletion causes early memory and learning deficits in APP/PS1 mice. J Neurosci Off J Soc Neurosci. 2014;34(26):8845–54.

    Article  CAS  Google Scholar 

  82. 82.

    Moran O, Conti F, Tammaro P. Sodium channel heterologous expression in mammalian cells and the role of the endogenous beta1-subunits. Neurosci Lett. 2003;336(3):175–9.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Van Eldik LJ, Griffin WS. S100 beta expression in Alzheimer’s disease: relation to neuropathology in brain regions. Biochim Biophys Acta. 1994;1223(3):398–403.

    PubMed  Article  Google Scholar 

  84. 84.

    Mori T, Koyama N, Arendash GW, Horikoshi-Sakuraba Y, Tan J, Town T. Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer’s disease. Glia. 2010;58(3):300–14.

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Thundyil J, Lim K-L. DAMPs and neurodegeneration. Ageing Res Rev. 2015;24(Pt A):17–28.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Hauser CJ, Sursal T, Rodriguez EK, Appleton PT, Zhang Q, Itagaki K. Mitochondrial damage associated molecular patterns from femoral reamings activate neutrophils through formyl peptide receptors and P44/42 MAP kinase. J Orthop Trauma. 2010;24(9):534–8.

    PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Barbalat R, Ewald SE, Mouchess ML, Barton GM. Nucleic acid recognition by the innate immune system. Annu Rev Immunol. 2011;29(1):185–214.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Luong M, Zhang Y, Chamberlain T, Zhou T, Wright JF, Dower K, et al. Stimulation of TLR4 by recombinant HSP70 requires structural integrity of the HSP70 protein itself. J Inflamm Lond Engl. 2012;9(1):11.

    CAS  Article  Google Scholar 

  89. 89.

    Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem. 2002;277(17):15028–34.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol. 2000;12(11):1539–46.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Yang Y, Turner RS, Gaut JR. The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion. J Biol Chem. 1998;273(40):25552–5.

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Dickey C, Kraft C, Jinwal U, Koren J, Johnson A, Anderson L, et al. Aging analysis reveals slowed tau turnover and enhanced stress response in a mouse model of tauopathy. Am J Pathol. 2009;174(1):228–38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007;30(10):527–35.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G. Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophys Acta. 2010;1802(1):2–10.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Mao P, Manczak M, Calkins MJ, Truong Q, Reddy TP, Reddy AP, et al. Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer’s disease: implications for neuroprotection and lifespan extension. Hum Mol Genet. 2012;21(13):2973–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, et al. Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging. 2008;29(9):1334–47.

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Wenk GL, Parsons CG, Danysz W. Potential role of N-methyl-d-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine. Behav Pharmacol. 2006;17(5–6):411–24.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Farso MC, O’Shea RD, Beart PM. Evidence group I mGluR drugs modulate the activation profile of lipopolysaccharide-exposed microglia in culture. Neurochem Res. 2009;34(10):1721–8.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Kaushal V, Schlichter LC. Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci Off J Soc Neurosci. 2008;28(9):2221–30.

    CAS  Article  Google Scholar 

  100. 100.

    Beaulieu J-M, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63(1):182–217.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Lee SP, So CH, Rashid AJ, Varghese G, Cheng R, Lança AJ, et al. Dopamine D1 and D2 receptor Co-activation generates a novel phospholipase C-mediated calcium signal. J Biol Chem. 2004;279(34):35671–8.

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Suzuki T, Hide I, Matsubara A, Hama C, Harada K, Miyano K, et al. Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. J Neurosci Res. 2006;83(8):1461–70.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Carnevale D, De Simone R, Minghetti L. Microglia-neuron interaction in inflammatory and degenerative diseases: role of cholinergic and noradrenergic systems. CNS Neurol Disord Drug Targets. 2007;6(6):388–97.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, et al. Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA. 2010;107(13):6058–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Tanaka KF, Kashima H, Suzuki H, Ono K, Sawada M. Existence of functional beta1- and beta2-adrenergic receptors on microglia. J Neurosci Res. 2002;70(2):232–7.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Heneka MT, Galea E, Gavriluyk V, Dumitrescu-Ozimek L, Daeschner J, O’Banion MK, et al. Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer’s disease. J Neurosci Off J Soc Neurosci. 2002;22(7):2434–42.

    CAS  Google Scholar 

  107. 107.

    Heneka MT, Gavrilyuk V, Landreth GE, O’Banion MK, Weinberg G, Feinstein DL. Noradrenergic depletion increases inflammatory responses in brain: effects on IkappaB and HSP70 expression. J Neurochem. 2003;85(2):387–98.

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, et al. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci Off J Soc Neurosci. 2006;26(5):1343–54.

    CAS  Article  Google Scholar 

  109. 109.

    Makar TK, Bever CT, Singh IS, Royal W, Sahu SN, Sura TP, et al. Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. J Neuroimmunol. 2009;210(1–2):40–51.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Zhang J, Malik A, Choi HB, Ko RWY, Dissing-Olesen L, MacVicar BA. Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron. 2014;82(1):195–207.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Orre M, Kamphuis W, Osborn LM, Jansen AHP, Kooijman L, Bossers K, et al. Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol Aging. 2014;35(12):2746–60.

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Su F, Bai F, Zhang Z. Inflammatory cytokines and Alzheimer’s disease: a review from the perspective of genetic polymorphisms. Neurosci Bull. 2016;32(5):469–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med. 2012;2(1):a006346.

    PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Dursun E, Gezen-Ak D, Hanağası H, Bilgiç B, Lohmann E, Ertan S, et al. The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer’s disease, mild cognitive impairment or Parkinson’s disease. J Neuroimmunol. 2015;15(283):50–7.

    Article  CAS  Google Scholar 

  115. 115.

    Sciacca FL, Ferri C, Licastro F, Veglia F, Biunno I, Gavazzi A, et al. Interleukin-1B polymorphism is associated with age at onset of Alzheimer’s disease. Neurobiol Aging. 2003;24(7):927–31.

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Forlenza OV, Diniz BS, Talib LL, Mendonça VA, Ojopi EB, Gattaz WF, et al. Increased serum IL-1beta level in Alzheimer’s disease and mild cognitive impairment. Dement Geriatr Cogn Disord. 2009;28(6):507–12.

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Payão SLM, Gonçalves GM, de Labio RW, Horiguchi L, Mizumoto I, Rasmussen LT, et al. Association of interleukin 1β polymorphisms and haplotypes with Alzheimer’s disease. J Neuroimmunol. 2012;247(1–2):59–62.

    PubMed  Article  CAS  Google Scholar 

  118. 118.

    Yuan H, Xia Q, Ge P, Wu S. Genetic polymorphism of interleukin 1β-511C/T and susceptibility to sporadic Alzheimer’s disease: a meta-analysis. Mol Biol Rep. 2013;40(2):1827–34.

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Yin Y, Liu Y, Pan X, Chen R, Li P, Wu H-J, et al. Interleukin-1β promoter polymorphism enhances the risk of sleep disturbance in Alzheimer’s disease. PloS One. 2016;11(3):e0149945.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. 120.

    Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity. 2003;19(5):641–4.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Zhu X-C, Tan L, Jiang T, Tan M-S, Zhang W, Yu J-T. Association of IL-12A and IL-12B polymorphisms with Alzheimer’s disease susceptibility in a Han Chinese population. J Neuroimmunol. 2014;274(1–2):180–4.

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Vom Berg J, Prokop S, Miller KR, Obst J, Kälin RE, Lopategui-Cabezas I, et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med. 2012;18(12):1812–9.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Guillot-Sestier M-V, Doty KR, Gate D, Rodriguez J, Leung BP, Rezai-Zadeh K, et al. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron. 2015;85(3):534–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron. 2015;85(3):519–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    van der Wal EA, Gómez-Pinilla F, Cotman CW. Transforming growth factor-beta 1 is in plaques in Alzheimer and Down pathologies. Neuroreport. 1993;4(1):69–72.

    PubMed  Article  Google Scholar 

  126. 126.

    Chao CC, Ala TA, Hu S, Crossley KB, Sherman RE, Peterson PK, et al. Serum cytokine levels in patients with Alzheimer’s disease. Clin Diagn Lab Immunol. 1994;1(4):433–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Zetterberg H, Andreasen N, Blennow K. Increased cerebrospinal fluid levels of transforming growth factor-beta1 in Alzheimer’s disease. Neurosci Lett. 2004;367(2):194–6.

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, et al. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med. 2001;7(5):612–8.

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Chalmers KA, Love S. Neurofibrillary tangles may interfere with Smad 2/3 signaling in neurons. J Neuropathol Exp Neurol. 2007;66(2):158–67.

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Le Thuc O, Blondeau N, Nahon JL, Rovère C. The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects. Ann N Y Acad Sci. 2015;1351(1):127–40.

    PubMed  Article  CAS  Google Scholar 

  131. 131.

    Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA. 1998;95(18):10896–901.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006;9(7):917–24.

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Cho SH, Sun B, Zhou Y, Kauppinen TM, Halabisky B, Wes P, et al. CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J Biol Chem. 2011;286(37):32713–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Nash KR, Lee DC, Hunt JB, Morganti JM, Selenica ML, Moran P, et al. Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy. Neurobiol Aging. 2013;34(6):1540–8.

    CAS  PubMed  Article  Google Scholar 

  136. 136.

    Lee DC, Rizer J, Selenica M-LB, Reid P, Kraft C, Johnson A, et al. LPS-induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J Neuroinflamm. 2010;7:56.

    Article  CAS  Google Scholar 

  137. 137.

    Duan RS, Yang X, Chen ZG, Lu MO, Morris C, Winblad B, et al. Decreased fractalkine and increased IP-10 expression in aged brain of APPswe transgenic mice. Neurochem Res. 2008;33(6):1085–9.

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Kim T-S, Lim H-K, Lee JY, Kim D-J, Park S, Lee C, et al. Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci Lett. 2008;436(2):196–200.

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Sokolova A, Hill MD, Rahimi F, Warden LA, Halliday GM, Shepherd CE. Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer’s disease. Brain Pathol. 2009;19(3):392–8.

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    He M, Dong H, Huang Y, Lu S, Zhang S, Qian Y, et al. Astrocyte-derived CCL2 is associated with m1 activation and recruitment of cultured microglial cells. Cell Physiol Biochem. 2016;38(3):859–70.

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Galimberti D, Fenoglio C, Lovati C, Venturelli E, Guidi I, Corrà B, et al. Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer’s disease. Neurobiol Aging. 2006;27(12):1763–8.

    CAS  PubMed  Article  Google Scholar 

  142. 142.

    Westin K, Buchhave P, Nielsen H, Minthon L, Janciauskiene S, Hansson O. CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer’s disease. PLoS One. 2012;7(1):1–6.

    Article  CAS  Google Scholar 

  143. 143.

    Kiyota T, Yamamoto M, Xiong H, Lambert MP, Klein WL, Gendelman HE, et al. CCL2 accelerates microglia-mediated A? Oligomer formation and progression of neurocognitive dysfunction. PLoS One. 2009;4(7):e6197.

  144. 144.

    Vodovotz Y, Lucia MS, Flanders KC, Chesler L, Xie QW, Smith TW, et al. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer’s disease. J Exp Med. 1996;184(4):1425–33.

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Heneka MT, Wiesinger H, Dumitrescu-Ozimek L, Riederer P, Feinstein DL, Klockgether T. Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J Neuropathol Exp Neurol. 2001;60(9):906–16.

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Kummer MP, Hermes M, Delekarte A, Hammerschmidt T, Kumar S, Terwel D, et al. Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron. 2011;71(5):833–44.

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25(2):181–213.

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Turrigiano GG. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell. 2008;135(3):422–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440(7087):1054–9.

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ. Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci USA. 2008;105(44):17151–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Dissing-Olesen L, LeDue JM, Rungta RL, Hefendehl JK, Choi HB, MacVicar BA. Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth. J Neurosci Off J Soc Neurosci. 2014;34(32):10511–27.

    Article  CAS  Google Scholar 

  152. 152.

    Eyo UB, Peng J, Swiatkowski P, Mukherjee A, Bispo A, Wu L-J. Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J Neurosci Off J Soc Neurosci. 2014;34(32):10528–40.

    Article  CAS  Google Scholar 

  153. 153.

    Fontainhas AM, Wang M, Liang KJ, Chen S, Mettu P, Damani M, et al. Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PloS One. 2011;6(1):e15973.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Li Y, Du X-F, Liu C-S, Wen Z-L, Du J-L. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev Cell. 2012;23(6):1189–202.

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Ji K, Akgul G, Wollmuth LP, Tsirka SE. Microglia actively regulate the number of functional synapses. PloS One. 2013;8(2):e56293.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Bisht K, Sharma KP, Lecours C, Sánchez MG, El Hajj H, Milior G, et al. Dark microglia: a new phenotype predominantly associated with pathological states. Glia. 2016;64(5):826–39.

    PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Vasek MJ, Garber C, Dorsey D, Durrant DM, Bollman B, Soung A, et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature. 2016;534(7608):538–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, Yin X, et al. Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci Off J Soc Neurosci. 2012;32(34):11706–15.

    CAS  Article  Google Scholar 

  159. 159.

    Chen Z, Jalabi W, Hu W, Park H-J, Gale JT, Kidd GJ, et al. Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain. Nat Commun. 2014;22(5):4486.

    Google Scholar 

  160. 160.

    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352(6286):712–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442(7105):916–9.

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442(7105):920–4.

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med. 2010;207(1):117–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang H-Y, et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell. 2016;165(4):921–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165.

    Abiega O, Beccari S, Diaz-Aparicio I, Nadjar A, Layé S, Leyrolle Q, et al. Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling. PLoS Biol. 2016;14(5):e1002466.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  166. 166.

    Sierra A, Encinas JM, Deudero JJP, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7(4):483–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Boulanger LM. Immune proteins in brain development and synaptic plasticity. Neuron. 2009;64(1):93–109.

    CAS  PubMed  Article  Google Scholar 

  168. 168.

    Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64(1):61–78.

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Gemma C, Bachstetter AD, Cole MJ, Fister M, Hudson C, Bickford PC. Blockade of caspase-1 increases neurogenesis in the aged hippocampus. Eur J Neurosci. 2007;26(10):2795–803.

    PubMed  Article  Google Scholar 

  170. 170.

    Green HF, Nolan YM. Unlocking mechanisms in interleukin-1β-induced changes in hippocampal neurogenesis–a role for GSK-3β and TLX. Transl Psychiatry. 2012;20(2):e194.

    Article  CAS  Google Scholar 

  171. 171.

    Guadagno J, Swan P, Shaikh R, Cregan SP. Microglia-derived IL-1β triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells. Cell Death Dis. 2015;4(6):e1779.

    Article  CAS  Google Scholar 

  172. 172.

    Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA. 2008;105(2):751–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Wu MD, Montgomery SL, Rivera-Escalera F, Olschowka JA, O’Banion MK. Sustained IL-1β expression impairs adult hippocampal neurogenesis independent of IL-1 signaling in nestin + neural precursor cells. Brain Behav Immun. 2013;32:9–18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. 174.

    Zhang K, Xu H, Cao L, Li K, Huang Q. Interleukin-1β inhibits the differentiation of hippocampal neural precursor cells into serotonergic neurons. Brain Res. 2013;15(1490):193–201.

    Article  CAS  Google Scholar 

  175. 175.

    Zunszain PA, Anacker C, Cattaneo A, Choudhury S, Musaelyan K, Myint AM, et al. Interleukin-1β: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2012;37(4):939–49.

    CAS  Article  Google Scholar 

  176. 176.

    Biber K, Neumann H, Inoue K, Boddeke HWGM. Neuronal “On” and “Off” signals control microglia. Trends Neurosci. 2007;30(11):596–602.

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Hellwig S, Heinrich A, Biber K. The brain’s best friend: microglial neurotoxicity revisited. Front Cell Neurosci. 2013;7:71.

    PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Maggi L, Scianni M, Branchi I, D’Andrea I, Lauro C, Limatola C. CX(3)CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Front Cell Neurosci. 2011;5:22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    Reshef R, Kreisel T, Beroukhim Kay D, Yirmiya R. Microglia and their CX3CR1 signaling are involved in hippocampal-but not olfactory bulb-related memory and neurogenesis. Brain Behav Immun. 2014;41:239–50.

    CAS  PubMed  Article  Google Scholar 

  180. 180.

    Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, et al. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci Off J Soc Neurosci. 2011;31(45):16241–50.

    CAS  Article  Google Scholar 

  181. 181.

    Sellner S, Paricio-Montesinos R, Spieß A, Masuch A, Erny D, Harsan LA, et al. Microglial CX3CR1 promotes adult neurogenesis by inhibiting Sirt 1/p65 signaling independent of CX3CL1. Acta Neuropathol Commun. 2016;4(1):102.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  182. 182.

    Corona AW, Norden DM, Skendelas JP, Huang Y, O’Connor JC, Lawson M, et al. Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX(3)CR1)-deficient mice. Brain Behav Immun. 2013;31:134–42.

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Bachstetter AD, Morganti JM, Jernberg J, Schlunk A, Mitchell SH, Brewster KW, et al. Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol Aging. 2011;32(11):2030–44.

    CAS  PubMed  Article  Google Scholar 

  184. 184.

    Damani MR, Zhao L, Fontainhas AM, Amaral J, Fariss RN, Wong WT. Age-related alterations in the dynamic behavior of microglia. Aging Cell. 2011;10(2):263–76.

    CAS  PubMed  Article  Google Scholar 

  185. 185.

    Hefendehl JK, Neher JJ, Sühs RB, Kohsaka S, Skodras A, Jucker M. Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell. 2014;13(1):60–9.

    CAS  PubMed  Article  Google Scholar 

  186. 186.

    Eggen BJL, Raj D, Hanisch U-K, Boddeke HWGM. Microglial phenotype and adaptation. J Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol. 2013;8(4):807–23.

    CAS  Article  Google Scholar 

  187. 187.

    Gemma C, Bachstetter AD. The role of microglia in adult hippocampal neurogenesis. Front Cell Neurosci. 2013;22(7):229.

    Google Scholar 

  188. 188.

    Harry GJ. Microglia during development and aging. Pharmacol Ther. 2013;139(3):313–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    Niraula A, Sheridan JF, Godbout JP. Microglia priming with aging and stress. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2017;42(1):318–33.

    Article  Google Scholar 

  190. 190.

    Perry VH. Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol (Berl). 2010;120(3):277–86.

    CAS  Article  Google Scholar 

  191. 191.

    Raj DDA, Jaarsma D, Holtman IR, Olah M, Ferreira FM, Schaafsma W, et al. Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol Aging. 2014;35(9):2147–60.

    CAS  PubMed  Article  Google Scholar 

  192. 192.

    Wong WT. Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Front Cell Neurosci. 2013;7:22.

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    Dong X, Wang Y, Qin Z. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009;30(4):379–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL. The time course of glutamate in the synaptic cleft. Science. 1992;258(5087):1498–501.

    CAS  PubMed  Article  Google Scholar 

  195. 195.

    Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65(1):1–105.

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    Holmseth S, Scott HA, Real K, Lehre KP, Leergaard TB, Bjaalie JG, et al. The concentrations and distributions of three C-terminal variants of the GLT1 (EAAT2; slc1a2) glutamate transporter protein in rat brain tissue suggest differential regulation. Neuroscience. 2009;162(4):1055–71.

    CAS  PubMed  Article  Google Scholar 

  197. 197.

    Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2011;13(1):22–37.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  198. 198.

    Scott HA, Gebhardt FM, Mitrovic AD, Vandenberg RJ, Dodd PR. Glutamate transporter variants reduce glutamate uptake in Alzheimer’s disease. Neurobiol Aging. 2011;32(3):553.e1–11.

  199. 199.

    Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, Quack G. Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1-40). Brain Res. 2002;958(1):210–21.

    CAS  PubMed  Article  Google Scholar 

  200. 200.

    Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 2011;12(12):723–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta. 2016;1862(5):887–900.

    CAS  PubMed  Article  Google Scholar 

  202. 202.

    Montagne A, Zhao Z, Zlokovic BV. Alzheimer’s disease: a matter of blood–brain barrier dysfunction? J Exp Med. 2017;214(11):3151–69.

  203. 203.

    Rustenhoven J, Jansson D, Smyth LC, Dragunow M. Brain pericytes as mediators of neuroinflammation. Trends Pharmacol Sci. 2017;38(3):291–304.

    CAS  PubMed  Article  Google Scholar 

  204. 204.

    Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, et al. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood–brain barrier. J Clin Investig. 2000;106(12):1489–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. 205.

    Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, et al. Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med. 2007;13(9):1029–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, et al. RAGE mediates amyloid-beta peptide transport across the blood–brain barrier and accumulation in brain. Nat Med. 2003;9(7):907–13.

    CAS  PubMed  Article  Google Scholar 

  207. 207.

    Zlokovic BV, Yamada S, Holtzman D, Ghiso J, Frangione B. Clearance of amyloid beta-peptide from brain: transport or metabolism? Nat Med. 2000;6(7):718–9.

    Article  Google Scholar 

  208. 208.

    Selkoe DJ. Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis. 2001;3(1):75–80.

    CAS  PubMed  Article  Google Scholar 

  209. 209.

    Holtzman DM, Zlokovic B. Role of Aβ transport and clearance in the pathogenesis and treatment of Alzheimer’s disease. In: Sisodia SS, Tanzi RE editors. Alzheimer’s disease (Internet). Boston: Springer; 2007. pp 179–98. https://doi.org/10.1007/978-0-387-35135-3_11.

  210. 210.

    Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  211. 211.

    McManus RM, Heneka MT. Role of neuroinflammation in neurodegeneration: new insights. Alzheimers Res Ther. 2017;9(1):14.

    PubMed  PubMed Central  Article  Google Scholar 

  212. 212.

    Dunn N, Mullee M, Perry VH, Holmes C. Association between dementia and infectious disease: evidence from a case–control study. Alzheimer Dis Assoc Disord. 2005;19(2):91–4.

    PubMed  Article  Google Scholar 

  213. 213.

    Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2003;74(6):788–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  214. 214.

    Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73(10):768–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 215.

    Natalwala A, Potluri R, Uppal H, Heun R. Reasons for hospital admissions in dementia patients in Birmingham, UK, during 2002-2007. Dement Geriatr Cogn Disord. 2008;26(6):499–505.

    PubMed  Article  Google Scholar 

  216. 216.

    Fitzpatrick AL, Kuller LH, Lopez OL, Kawas CH, Jagust W. Survival following dementia onset: Alzheimer’s disease and vascular dementia. J Neurol Sci. 2005;15(229–230):43–9.

    Article  Google Scholar 

  217. 217.

    Foley NC, Affoo RH, Martin RE. A systematic review and meta-analysis examining pneumonia-associated mortality in dementia. Dement Geriatr Cogn Disord. 2015;39(1–2):52–67.

    PubMed  Article  Google Scholar 

  218. 218.

    Magaki S, Yong WH, Khanlou N, Tung S, Vinters HV. Comorbidity in dementia: update of an ongoing autopsy study. J Am Geriatr Soc. 2014;62(9):1722–8.

    PubMed  PubMed Central  Article  Google Scholar 

  219. 219.

    Tyas SL, Manfreda J, Strain LA, Montgomery PR. Risk factors for Alzheimer’s disease: a population-based, longitudinal study in Manitoba, Canada. Int J Epidemiol. 2001;30(3):590–7.

    CAS  PubMed  Article  Google Scholar 

  220. 220.

    Verreault R, Laurin D, Lindsay J, Serres GD. Past exposure to vaccines and subsequent risk of Alzheimer’s disease. CMAJ Can Med Assoc J. 2001;165(11):1495–8.

    CAS  Google Scholar 

  221. 221.

    Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF. Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol. 1991;33(4):224–7.

    CAS  PubMed  Article  Google Scholar 

  222. 222.

    Jamieson GA, Maitland NJ, Wilcock GK, Yates CM, Itzhaki RF. Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type. J Pathol. 1992;167(4):365–8.

    CAS  PubMed  Article  Google Scholar 

  223. 223.

    Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF. Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer’s disease patients. J Med Virol. 2005;75(2):300–6.

    PubMed  Article  Google Scholar 

  224. 224.

    Honjo K, van Reekum R, Verhoeff NPLG. Alzheimer’s disease and infection: do infectious agents contribute to progression of Alzheimer’s disease? Alzheimers Dement J Alzheimers Assoc. 2009;5(4):348–60.

    Article  Google Scholar 

  225. 225.

    Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet Lond Engl. 1997;349(9047):241–4.

    CAS  Article  Google Scholar 

  226. 226.

    Gérard HC, Wildt KL, Whittum-Hudson JA, Lai Z, Ager J, Hudson AP. The load of Chlamydia pneumoniae in the Alzheimer’s brain varies with APOE genotype. Microb Pathog. 2005;39(1–2):19–26.

    PubMed  Article  CAS  Google Scholar 

  227. 227.

    Gérard HC, Dreses-Werringloer U, Wildt KS, Deka S, Oszust C, Balin BJ, et al. Chlamydophila (Chlamydia) pneumoniae in the Alzheimer’s brain. FEMS Immunol Med Microbiol. 2006;48(3):355–66.

    PubMed  Article  CAS  Google Scholar 

  228. 228.

    Alonso R, Pisa D, Marina AI, Morato E, Rábano A, Carrasco L. Fungal infection in patients with Alzheimer’s disease. J Alzheimers Dis. 2014;41(1):301–11.

    CAS  PubMed  Google Scholar 

  229. 229.

    Alonso R, Pisa D, Rábano A, Rodal I, Carrasco L. Cerebrospinal fluid from Alzheimer’s disease patients contains fungal proteins and DNA. J Alzheimers Dis. 2015;47(4):873–6.

    CAS  PubMed  Article  Google Scholar 

  230. 230.

    Pisa D, Alonso R, Rábano A, Rodal I, Carrasco L. Different brain regions are infected with fungi in Alzheimer’s disease. Sci Rep. 2015;15(5):15015.

    Article  CAS  Google Scholar 

  231. 231.

    Pisa D, Alonso R, Juarranz A, Rábano A, Carrasco L. Direct visualization of fungal infection in brains from patients with Alzheimer’s disease. J Alzheimers Dis. 2015;43(2):613–24.

    CAS  PubMed  Google Scholar 

  232. 232.

    Jakobsson HE, Rodríguez-Piñeiro AM, Schütte A, Ermund A, Boysen P, Bemark M, et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep. 2015;16(2):164–77.

    CAS  PubMed  Article  Google Scholar 

  233. 233.

    Faden AI, Loane DJ. Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation? Neurother J Am Soc Exp Neurother. 2015;12(1):143–50.

    CAS  Article  Google Scholar 

  234. 234.

    Faden AI, Wu J, Stoica BA, Loane DJ. Progressive inflammation-mediated neurodegeneration after traumatic brain or spinal cord injury. Br J Pharmacol. 2016;173(4):681–91.

    CAS  PubMed  Article  Google Scholar 

  235. 235.

    Smith DH, Johnson VE, Stewart W. Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat Rev Neurol. 2013;9(4):211–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  236. 236.

    Washington PM, Villapol S, Burns MP. Polypathology and dementia after brain trauma: does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy? Exp Neurol. 2016;275(Pt 3):381–8.

    PubMed  Article  Google Scholar 

  237. 237.

    Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry. 2003;74(7):857–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  238. 238.

    Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A, et al. Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of case–control studies. EURODEM Risk Factors Research Group. Int J Epidemiol. 1991;20(Suppl 2):S28–35.

    PubMed  Article  Google Scholar 

  239. 239.

    Johnson VE, Stewart W, Smith DH. Widespread τ and amyloid-β pathology many years after a single traumatic brain injury in humans. Brain Pathol Zurich Switz. 2012;22(2):142–9.

    CAS  Article  Google Scholar 

  240. 240.

    Smith DH, Chen XH, Nonaka M, Trojanowski JQ, Lee VM, Saatman KE, et al. Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig. J Neuropathol Exp Neurol. 1999;58(9):982–92.

    CAS  PubMed  Article  Google Scholar 

  241. 241.

    Bennett RE, Esparza TJ, Lewis HA, Kim E, Mac Donald CL, Sullivan PM, et al. Human apolipoprotein E4 worsens acute axonal pathology but not amyloid-β immunoreactivity after traumatic brain injury in 3xTG-AD mice. J Neuropathol Exp Neurol. 2013;72(5):396–403.

    CAS  PubMed  Article  Google Scholar 

  242. 242.

    Chen X-H, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Smith DH. Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol. 2004;165(2):357–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  243. 243.

    Iwata A, Chen X-H, McIntosh TK, Browne KD, Smith DH. Long-term accumulation of amyloid-beta in axons following brain trauma without persistent upregulation of amyloid precursor protein genes. J Neuropathol Exp Neurol. 2002;61(12):1056–68.

    CAS  PubMed  Article  Google Scholar 

  244. 244.

    Shishido H, Kishimoto Y, Kawai N, Toyota Y, Ueno M, Kubota T, et al. Traumatic brain injury accelerates amyloid-β deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer’s disease. Neurosci Lett. 2016;26(629):62–7.

    Article  CAS  Google Scholar 

  245. 245.

    Kane MJ, Angoa-Pérez M, Briggs DI, Viano DC, Kreipke CW, Kuhn DM. A mouse model of human repetitive mild traumatic brain injury. J Neurosci Methods. 2012;203(1):41–9.

    PubMed  Article  Google Scholar 

  246. 246.

    Luo J, Nguyen A, Villeda S, Zhang H, Ding Z, Lindsey D, et al. Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury. Front Neurol (Internet). 2014;5:12. https://doi.org/10.3389/fneur.2014.00012.

  247. 247.

    McAteer KM, Corrigan F, Thornton E, Turner RJ, Vink R. Short and long term behavioral and pathological changes in a novel rodent model of repetitive mild traumatic brain injury. PLOS One. 2016;11(8):e0160220.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  248. 248.

    Petraglia AL, Plog BA, Dayawansa S, Dashnaw ML, Czerniecka K, Walker CT, et al. The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy. Surg Neurol Int. 2014;5:184.

    PubMed  PubMed Central  Article  Google Scholar 

  249. 249.

    Gerson J, Castillo-Carranza DL, Sengupta U, Bodani R, Prough DS, DeWitt DS, et al. Tau oligomers derived from traumatic brain injury cause cognitive impairment and accelerate onset of pathology in htau mice. J Neurotrauma. 2016;33(22):2034–43.

    PubMed  PubMed Central  Article  Google Scholar 

  250. 250.

    Hillier V, Salib E. A case–control study of smoking and Alzheimer’s disease. Int J Geriatr Psychiatry. 1997;12(3):295–300.

    CAS  PubMed  Article  Google Scholar 

  251. 251.

    Brenner DE, Kukull WA, van Belle G, Bowen JD, McCormick WC, Teri L, et al. Relationship between cigarette smoking and Alzheimer’s disease in a population-based case–control study. Neurology. 1993;43(2):293–300.

    CAS  PubMed  Article  Google Scholar 

  252. 252.

    Reitz C, den Heijer T, van Duijn C, Hofman A, Breteler MMB. Relation between smoking and risk of dementia and Alzheimer disease: The Rotterdam Study. Neurology. 2007;69(10):998–1005.

    CAS  PubMed  Article  Google Scholar 

  253. 253.

    Aggarwal NT, Bienias JL, Bennett DA, Wilson RS, Morris MC, Schneider JA, et al. The relation of cigarette smoking to incident Alzheimer’s disease in a biracial urban community population. Neuroepidemiology. 2006;26(3):140–6.

    PubMed  Article  Google Scholar 

  254. 254.

    Cataldo JK, Prochaska JJ, Glantz SA. Cigarette smoking is a risk factor for Alzheimer’s disease: an analysis controlling for tobacco industry affiliation. J Alzheimers Dis. 2010;19(2):465–80.

    PubMed  PubMed Central  Article  Google Scholar 

  255. 255.

    Tyas SL, White LR, Petrovitch H, Webster Ross G, Foley DJ, Heimovitz HK, et al. Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study. Neurobiol Aging. 2003;24(4):589–96.

    PubMed  Article  Google Scholar 

  256. 256.

    Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011;10(9):819–28.

    PubMed  PubMed Central  Article  Google Scholar 

  257. 257.

    Giunta B, Deng J, Jin J, Sadic E, Rum S, Zhou H, et al. Evaluation of how cigarette smoke is a direct risk factor for Alzheimer’s disease. Technol Innov. 2012;14(1):39–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  258. 258.

    Moreno-Gonzalez I, Estrada LD, Sanchez-Mejias E, Soto C. Smoking exacerbates amyloid pathology in a mouse model of Alzheimer’s disease. Nat Commun. 2013;4:1495.

    PubMed  Article  CAS  Google Scholar 

  259. 259.

    Gons RAR, van Norden AGW, de Laat KF, van Oudheusden LJB, van Uden IWM, Zwiers MP, et al. Cigarette smoking is associated with reduced microstructural integrity of cerebral white matter. Brain J Neurol. 2011;134(Pt 7):2116–24.

    Article  Google Scholar 

  260. 260.

    Kenche H, Baty CJ, Vedagiri K, Shapiro SD, Blumental-Perry A. Cigarette smoking affects oxidative protein folding in endoplasmic reticulum by modifying protein disulfide isomerase. FASEB J Off Publ Fed Am Soc Exp Biol. 2013;27(3):965–77.

    CAS  Google Scholar 

  261. 261.

    Shen C, Chen Y, Liu H, Zhang K, Zhang T, Lin A, et al. Hydrogen peroxide promotes Aβ production through JNK-dependent activation of γ-Secretase. J Biol Chem. 2008;283(25):17721–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  262. 262.

    Ho Y-S, Yang X, Yeung S-C, Chiu K, Lau C-F, Tsang AW-T, et al. Cigarette smoking accelerated brain aging and induced pre-Alzheimer-like neuropathology in rats. PLOS One. 2012;7(5):e36752.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  263. 263.

    Seet RCS, Lee C-YJ, Loke WM, Huang SH, Huang H, Looi WF, et al. Biomarkers of oxidative damage in cigarette smokers: which biomarkers might reflect acute versus chronic oxidative stress? Free Radic Biol Med. 2011;50(12):1787–93.

    CAS  PubMed  Article  Google Scholar 

  264. 264.

    Baldeiras I, Santana I, Proença MT, Garrucho MH, Pascoal R, Rodrigues A, et al. Oxidative damage and progression to Alzheimer’s disease in patients with mild cognitive impairment. J Alzheimers Dis. 2010;21(4):1165–77.

    CAS  PubMed  Article  Google Scholar 

  265. 265.

    Hellström-Lindahl E, Mousavi M, Ravid R, Nordberg A. Reduced levels of Abeta 40 and Abeta 42 in brains of smoking controls and Alzheimer’s patients. Neurobiol Dis. 2004;15(2):351–60.

    PubMed  Article  CAS  Google Scholar 

  266. 266.

    Gao J, Adam B-L, Terry AV. Evaluation of nicotine and cotinine analogs as potential neuroprotective agents for Alzheimer’s disease. Bioorg Med Chem Lett. 2014;24(6):1472–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  267. 267.

    Rosa AO, Egea J, Gandía L, López MG, García AG. Neuroprotection by nicotine in hippocampal slices subjected to oxygen-glucose deprivation: involvement of the alpha7 nAChR subtype. J Mol Neurosci MN. 2006;30(1–2):61–2.

    CAS  PubMed  Article  Google Scholar 

  268. 268.

    Nordberg A, Hellström-Lindahl E, Lee M, Johnson M, Mousavi M, Hall R, et al. Chronic nicotine treatment reduces beta-amyloidosis in the brain of a mouse model of Alzheimer’s disease (APPsw). J Neurochem. 2002;81(3):655–8.

    CAS  PubMed  Article  Google Scholar 

  269. 269.

    Kihara T, Shimohama S, Sawada H, Kimura J, Kume T, Kochiyama H, et al. Nicotinic receptor stimulation protects neurons against beta-amyloid toxicity. Ann Neurol. 1997;42(2):159–63.

    CAS  PubMed  Article  Google Scholar 

  270. 270.

    Ono K, Hasegawa K, Yamada M, Naiki H. Nicotine breaks down preformed Alzheimer’s beta-amyloid fibrils in vitro. Biol Psychiatry. 2002;52(9):880–6.

    CAS  PubMed  Article  Google Scholar 

  271. 271.

    Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH, et al. Patients with Alzheimer’s disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci USA. 2001;98(6):3440–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  272. 272.

    Booth FW, Laye MJ, Lees SJ, Rector RS, Thyfault JP. Reduced physical activity and risk of chronic disease: the biology behind the consequences. Eur J Appl Physiol. 2008;102(4):381–90.

    PubMed  Article  Google Scholar 

  273. 273.

    Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010;67(1):71–9.

    PubMed  PubMed Central  Article  Google Scholar 

  274. 274.

    Nascimento CMC, Pereira JR, de Andrade LP, Garuffi M, Talib LL, Forlenza OV, et al. Physical exercise in MCI elderly promotes reduction of pro-inflammatory cytokines and improvements on cognition and BDNF peripheral levels. Curr Alzheimer Res. 2014;11(8):799–805.

    PubMed  Article  CAS  Google Scholar 

  275. 275.

    Radak Z, Hart N, Sarga L, Koltai E, Atalay M, Ohno H, et al. Exercise plays a preventive role against Alzheimer’s disease. J Alzheimers Dis. 2010;20(3):777–83.

    PubMed  Article  Google Scholar 

  276. 276.

    Jensen CS, Hasselbalch SG, Waldemar G, Simonsen AH. Biochemical markers of physical exercise on mild cognitive impairment and dementia: systematic review and perspectives. Front Neurol. 2015;6:187.

    PubMed  PubMed Central  Article  Google Scholar 

  277. 277.

    Cheng S-T, Chow PK, Song Y-Q, Yu ECS, Chan ACM, Lee TMC, et al. Mental and physical activities delay cognitive decline in older persons with dementia. Am J Geriatr Psychiatry Off J Am Assoc Geriatr Psychiatry. 2014;22(1):63–74.

    CAS  Article  Google Scholar 

  278. 278.

    Sofi F, Valecchi D, Bacci D, Abbate R, Gensini GF, Casini A, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med. 2011;269(1):107–17.

    CAS  PubMed  Article  Google Scholar 

  279. 279.

    Sampaio A, Marques EA, Mota J, Carvalho J. Effects of a multicomponent exercise program in institutionalized elders with Alzheimer’s disease. Dement Lond Engl. 2016. https://doi.org/10.1177/1471301216674558.

  280. 280.

    Küster OC, Fissler P, Laptinskaya D, Thurm F, Scharpf A, Woll A, et al. Cognitive change is more positively associated with an active lifestyle than with training interventions in older adults at risk of dementia: a controlled interventional clinical trial. BMC Psychiatry. 2016;16(1):315.

    PubMed  PubMed Central  Article  Google Scholar 

  281. 281.

    Smith JC, Nielson KA, Woodard JL, Seidenberg M, Rao SM. Physical activity and brain function in older adults at increased risk for Alzheimer’s disease. Brain Sci. 2013;3(1):54–83.

    PubMed  PubMed Central  Article  Google Scholar 

  282. 282.

    Rovio S, Kåreholt I, Helkala E-L, Viitanen M, Winblad B, Tuomilehto J, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol. 2005;4(11):705–11.

    PubMed  Article  Google Scholar 

  283. 283.

    Schuit AJ, Feskens EJ, Launer LJ, Kromhout D. Physical activity and cognitive decline, the role of the apolipoprotein e4 allele. Med Sci Sports Exerc. 2001;33(5):772–7.

    CAS  PubMed  Article  Google Scholar 

  284. 284.

    Etnier JL, Caselli RJ, Reiman EM, Alexander GE, Sibley BA, Tessier D, et al. Cognitive performance in older women relative to ApoE-epsilon4 genotype and aerobic fitness. Med Sci Sports Exerc. 2007;39(1):199–207.

    CAS  PubMed  Article  Google Scholar 

  285. 285.

    Cheng S-T, Chow PK, Song Y-Q, Yu ECS, Chan ACM, Lee TMC, et al. Mental and physical activities delay cognitive decline in older persons with dementia. Am J Geriatr Psychiatry Off J Am Assoc Geriatr Psychiatry. 2014;22(1):63–74.

    CAS  Article  Google Scholar 

  286. 286.

    Podewils LJ, Guallar E, Kuller LH, Fried LP, Lopez OL, Carlson M, et al. Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am J Epidemiol. 2005;161(7):639–51.

    PubMed  Article  Google Scholar 

  287. 287.

    Eggermont LHP, Swaab DF, Hol EM, Scherder EJA. Walking the line: a randomised trial on the effects of a short term walking programme on cognition in dementia. J Neurol Neurosurg Psychiatry. 2009;80(7):802–4.

    CAS  PubMed  Article  Google Scholar 

  288. 288.

    Kim B-K, Shin M-S, Kim C-J, Baek S-B, Ko Y-C, Kim Y-P. Treadmill exercise improves short-term memory by enhancing neurogenesis in amyloid beta-induced Alzheimer disease rats. J Exerc Rehabil. 2014;10(1):2–8.

    PubMed  PubMed Central  Article  Google Scholar 

  289. 289.

    Leem Y-H, Lim H-J, Shim S-B, Cho J-Y, Kim B-S, Han P-L. Repression of tau hyperphosphorylation by chronic endurance exercise in aged transgenic mouse model of tauopathies. J Neurosci Res. 2009;87(11):2561–70.

    CAS  PubMed  Article  Google Scholar 

  290. 290.

    Marosi K, Bori Z, Hart N, Sárga L, Koltai E, Radák Z, et al. Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience. 2012;13(226):21–8.

    Article  CAS  Google Scholar 

  291. 291.

    Um HS, Kang EB, Leem YH, Cho IH, Yang CH, Chae KR, et al. Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer’s disease in an NSE/APPsw-transgenic model. Int J Mol Med. 2008;22(4):529–39.

    CAS  PubMed  Google Scholar 

  292. 292.

    Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, Barberger-Gateau P, Dartigues JF. Intake of flavonoids and risk of dementia. Eur J Epidemiol. 2000;16(4):357–63.

    CAS  PubMed  Article