The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?

A strong genetic predisposition (60–80% of attributable risk) is present in Alzheimer’s disease (AD). In view of this major genetic component, identification of the genetic risk factors has been a major objective in the AD field with the ultimate aim to better understand the pathological processes. In this review, we present how the genetic risk factors are involved in APP metabolism, β-amyloid peptide production, degradation, aggregation and toxicity, innate immunity, and Tau toxicity. In addition, on the basis of the new genetic landscape, resulting from the recent high-throughput genomic approaches and emerging neurobiological information, we propose an over-arching model in which the focal adhesion pathway and the related cell signalling are key elements in AD pathogenesis. The core of the focal adhesion pathway links the physiological functions of amyloid precursor protein and Tau with the pathophysiological processes they are involved in. This model includes several entry points, fitting with the different origins for the disease, and supports the notion that dysregulation of synaptic plasticity is a central node in AD. Notably, our interpretation of the latest data from genome wide association studies complements other hypotheses already developed in the AD field, i.e., amyloid cascade, cellular phase or propagation hypotheses. Genetically driven synaptic failure hypothesis will need to be further tested experimentally within the general AD framework. Electronic supplementary material The online version of this article (10.1007/s00401-019-02004-0) contains supplementary material, which is available to authorized users.


ABCA7
ATP binding cassette subfamily A member 7, member of the 'A' subfamily of ATPbinding cassette transporters initially characterized by their capacity to transport lipids across membranes [134] -associated with plaque burden in AD brain [234]. Associated with Aβ deposition on in vivo imaging in human [13,292] -regulates APP processing resulting in an inhibition of Aβ production in vitro and in vivo in APP/PS1 mice, ABCA7 deletion facilitates the processing of APP to Aβ by increasing the levels of β-site APP cleaving enzyme 1 (BACE1) [35, 214,219] -stimulates phagocytosis in macrophages. ABCA7 loss results in 50% reduction of oAβ uptake by bone marrow-derived macrophages. ABCA7 loss doubles insoluble Aβ levels in J20 amyloidogenic mouse brain [110,133] -highly expressed in microglia. Its loss reduces microglia phagocytic clearance of amyloid-β [69] -associated with neurofibrillary tangle pathology in AD brain [287] -stimulates cellular cholesterol efflux to APOE discs [35] -ABCA7 rs3764650 associated with cortical and hippocampal atrophy in MCI [203] -genetic risk factor for posterior cortical atrophy (PCA), typically a rare variant of AD [221] -its loss-of-function variants are enriched in patients with AD [78] -Lysophosphatidylcholine is one of the major transport substrates for ABCA7 in the brain and this transport may be an important function of ABCA7 [254] ABI3 [108,237] ABI3 ABI family member 3, adaptor protein with a homeobox homology domain, a proline rich region and a SH3 domain -highly expressed in microglia cells, coexpressed with INPP5D, important role in actin cytoskeleton organization through participation in the WAVE2 complex, a complex that regulates multiple pathways leading to T cell activation [188,222,237] AC099552. 4 [25] AC099552.4 long non coding RNA 3 ACE [138] ACE Angiotensin I converting Enzyme, peptidase activity (reviewed in [127]) -ACE is an Aβ degrading enzyme [93,99,192,249,255] -ACE expression in AD brain tissue is associated with Aβ load and AD severity. Exposing SH-SY-5Y neurons to oAβ1-42 increases ACE level and activity, suggesting Abeta may upregulate ACE in AD [179] -CSF levels of the angiotensinconverting enzyme (ACE) are associated with Aβ levels [115] and LOAD risk [126] --in CSF, its levels but not activity is reduced in AD [179] CYB561 cytochrome b561 TANC2 tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2, synaptic scaffold protein -its overexpression in cultured neurons increases the density of dendritic spines and excitatory synapses [85] -involved in the capture of KIF1Adriven dense core vesicle (DCV) at dendritic spines [244] ADAM10 [108,138] ADAM10 the major α-secretase in the brain (reviewed in [213]) -component of the non-amyloidogenic pathway of APP metabolism (reviewed in [82]).
-over-expression of ADAM10 in mouse models can halt Aβ production and subsequent aggregation [199].
-two rare ADAM10 mutations segregating with disease in LOAD families increased Aβ plaque load in "Alzheimer-like" mice, with diminished α-secretase activity from the mutations likely the causal mechanism [130,248] -numerous and fundamental functions in the development of the embryonic brain and also in the homeostasis of adult neuronal networks. Mechanistically, ADAM10 controls these functions by utilizing unique postsynaptic substrates in the central nervous system, in particular synaptic cell adhesion molecules (reviewed in [213]) -sheds TREM2 to release soluble TREM2 ADAMTS1 [138] ADAMTS1 a disintegrin and metalloproteinase with thrombospondin motifs 1 -manifold overexpressed in brain of AD patients [176] -ADAMTS1 null female, but not male, exhibits a decline in synaptic protein levels [96] ADAMTS4 [108] ADAMTS4 a disintegrin and metalloproteinase with thrombospondin motifs 4 -generates N-truncated Aβ4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease [267] -could modulate Tau phosphorylation by cleaving Reelin (reviewed in [80] transmembrane sialic acid-binding immunoglobulin-like lectin that regulates innate immunity -its expression is increased in microglial cells in AD brain and inhibits microglial uptake of Aβ, which correlates with increased Aβ42 levels and plaque burden in AD patient brain [27,77] -the AD-risk allele increases the fulllength CD33M isoform containing the Exon2, which inhibit Aβ uptake [162,202]. The protective CD33m isoform is localized in peroxisome and may be protective because it does not localize to the cell membrane and neither interact directly with amyloid plaques nor engage in cell-surface signaling [ HBEGF heparin binding EGF like growth factor -HBEGF is an abundant neurotophic molecule of the brain regulating many higher brain functions [197] PICALM [90,108,138,144,184] PICALM phosphatidylinositol binding clathrin assembly protein, protein involved in clathrin mediated endocytosis (reviewed in [281]) -modifies Aβ toxicity in relationship with endocytosis in yeast [256] -regulates APP endocytosis, subsequent APP metabolism and Aβ production [252,280] -binds LC3, suggestive role in the trafficking APP-CTF from the endocytic pathway to the autophagic degradation pathway and in Aβ clearance [253] -regulates γ-secretase endocytosis and subsequent Aβ42/total Aβ ratio [120,121] -regulates Aβ blood-brain-barrier transcytosis and clearance [294] -regulates autophagy, Tau clearance and Tau toxicity [182] -co-localizes and coimmunoprecipitates with neurofibrillary tangles in human brains [10] -its levels correlates with Tau pathology and autophagy impairments in human brains [11] -strongly expressed in microglia [10] -regulates the endocytosis of synaptic vesicle proteins [ TM2 domain containing 3, the encoded protein contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily -preferentially influences uptake of Aβ aggregates during phagocytosis [86] -Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling [107] -By functional transcomplementation in Drosophila, the rare TM2D3 variant associated with LOAD, P155L, is a functionally damaging allele [107] TREM2 [20, 79,108,114,117,138,237] TREM2 triggering receptor expressed on myeloid cells 2, cell surface receptor of the immunoglobulin superfamily expressed on microglial cells (reviewed in [232,261]) -oAβ1-42 binds TREM2 on microglia and activates microglial response in a TREM2-dependent manner. The effect of the disease-associated mutations of TREM2 on its binding affinity to oAβ1-42 is debated [149,297] -its loss alters microglia phagocytosis, including phagocytosis of Aβ [111,136] -its TREM2 in amyloid mouse models (APPPS1-21, 5XFAD) results in defective microgliosis surrounding Aβ plaques with contradictory effects on the Aβ accumulation, whereas overexpression of TREM2 in the brain of APPswe/PS1dE9 mice ameliorated AD-related neuropathology [109,111,262,269] -in vitro, human stem cell-derived monocytes and transdifferentiated microglia-like cells reveal impaired amyloid plaque clearance upon heterozygous or homozygous loss of TREM2 [43] -its deficiency reduces the efficacy of immunotherapeutic amyloid clearance [278] -increased soluble TREM2 (sTREM2) CSF levels in AD patients that correlates with CSF Tau levels [198,246] -its loss exacerbates Tau pathology in P301S Tau mice [112]. Increased TREM2 ameliorates the pathological effects of activated microglia on GSK3-mediated neuronal Tau hyperphosphorylation via suppression of microglial inflammatory response [113] -In contrast, glial expression of TREM2/TYROBP exacerbates Taumediated neurodegeneration in Drosophila [223] -In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increases Tau pathology. The effect on microglial injury and Tauopathy would depend on the partial or complete loss of TREM2 [220] -Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway [295] -The AD-associated R47H TREM2 mutation have pleiotropic negative effects on microglia and myeloid cells that can be rescued by some TREM2activating antibodies [39, 40] -Structural analysis reveals that Arg47 plays a critical role in maintaining the structural features of the complementarity-determining region 2 (CDR2) loop and the putative positive ligand-interacting surface (PLIS), stabilizing conformations capable of ligand interaction [247]. However ADassociated TREM2 mutant would bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization [149] -APOE is a ligand of TREM2 whose binding to TREM2 can be blocked by the high-affinity binding of oAβ to TREM2. APOE binding is reduced for R47H TREM2 [14,15,149] TREML2 triggering receptor expressed on myeloid cells like 2, structurally related to the TREM famlily but does not signal though DAP12/TYROBP (reviewed in [66]) -oligomeric amyloid-β treatment upregulates TREML2 expression in primary microglia [296] -has AD-associated functional variants independent of TREM2 ones [21].
-The modulation of TREM2 or TREML2 levels has opposing effect on the proliferation of primary microglia, TREM2 or TREML2 downregulation respectively decrease or increase microglia proliferation [296].  ACTL6B actin like 6B, member of a family of actin-related proteins (ARPs) -subunit of neuron-specific chromatin remodeling complex [196] -its loss in mice results in synaptic plasticity and cocaine-associated memory defects that can be rescued by BDNF [270] AGFG2 ArfGAP with FG repeats 2, member of the HIV-1 Rev binding protein (HRB) family and plays a role in the Rev export pathway, which mediates the nucleocytoplasmic transfer of proteins and RNAs

AP4M1
adaptor related protein complex 4 subunit mu 1, subunit of the heterotetrameric AP-4 complex, which is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system -its mutation and AP-4 deficiency results in many clinical neuronal symptoms such as intellectual disability or hereditary spastic paraplegia… AZGP1 alpha-2-glycoprotein 1, zinc-binding, encode Zinc-α2-glycoprotein (ZAG), which is a major histocompatibility complex I molecule and a lipidmobilizing factor.

COPS6
COP9 signalosome subunit 6, one of the eight subunits of COP9 signalosome, regulator in multiple signaling pathways, whose structure is similar to that of the 19S regulatory particle of 26S proteasome. CASTOR family member 3, also named GATS -Lower expression in AD brain [122] GIGYF1 GRB10 interacting GYF protein 1, member of the gyf family of adaptor proteins -its Drosophila ortholog regulates neuronal autophagy [129] -regulates the Insulin signaling pathway [298] GJC3 gap junction protein gamma 3 -expressed in the myelinating glial cells [8] GNB2 G protein subunit beta 2, G proteins integrate signals between receptors and effector proteins ZCWPW1 / NYAP1 (cont'd)

GPC2
glypican 2, Glypicans are a group of cell-surface glycoproteins in which heparan sulfate (HS) glycosaminoglycan chains are covalently linked to a protein core, it can function as coreceptors for multiple signaling molecules.
-involved in neuronal cell adhesion and neurite outgrowth [