NeuroMolecular Medicine

, Volume 15, Issue 1, pp 25–48

Telomere Shortening and Alzheimer’s Disease

Authors

    • Department of Neurology, Lu’an People’s HospitalThe Lu’an Affiliated Hospital of Anhui Medical University
    • West Anhui Health Vocational College
    • Department of Pharmaceutical SciencesTexas A&M Health Science Center
  • Liang-Jun Yan
    • Department of Pharmacology & NeuroscienceUniversity of North Texas Health Science Center
  • Anna Ratka
    • Department of Pharmaceutical SciencesTexas A&M Health Science Center
Review Paper

DOI: 10.1007/s12017-012-8207-9

Cite this article as:
Cai, Z., Yan, L. & Ratka, A. Neuromol Med (2013) 15: 25. doi:10.1007/s12017-012-8207-9

Abstract

Telomeres, at the ends of chromosomes and strands of genetic material, become shorter as cells divide in the process of aging. Telomere length has been considered as a biological marker of age. Telomere length shortening has also been evidenced as the causable role in age-related neurodegenerative diseases, including Alzheimer’s disease (AD). It has been demonstrated that telomere shortening has been associated with cognitive impairment, amyloid pathology and hyper-phosphorylation of tau in AD and plays an important role in the pathogenesis of AD via the mechanism of oxidative stress and inflammation. However, it seems that there is no relationship between telomere shortening and AD. Therefore, it is essential for further clarification of telomere-related pathogenesis in AD.

Keywords

TelomereTelomere shorteningAlzheimer’s disease

Abbreviations

Aβ

Beta-amyloid

AD

Alzheimer’s disease

APP

Amyloid precursor protein

BACE

Beta-site APP-cleaving enzyme

BBB

Blood brain barrier

BFB

Breakage/fusion/bridge cycle

CADASIL

Cerebral autosomal dominant arteriopathy and leukoencephalopathy

COPD

Chronic obstructive pulmonary disease

Cox-2

Cyclooxygenase 2

CRP

C-reactive protein

CVD

Cardiovascular disease

eNOS

Endothelial nitric oxide synthase

ICAM-1

Inter-cellular adhesion molecule 1

ECM

Extracellular matrix

GM-CSF

Granulocyte–macrophage colony-stimulating factor

HD

Huntington’s disease

IFN

Interferon

LIF

Leukemia inhibitory factor

IL

Interleukin

IRAK

Interleukin-1 receptor-associated kinase

IRE

Iron-responsive element

LRP-1

Low-density lipoprotein receptor-related protein 1

MAPK

Mitogen-activated protein kinase

MCI

Mild cognitive impairment

MCP-1

Macrophage chemoattractant protein 1

MDS

Myelodysplastic syndromes

MMPs

Matrix metalloproteinases

MMSE

Mini Mental Status Examination

NF-κB

Nuclear factor-kappa B

NFT

Neurofibrillary tangles

NO

Nitric oxide

OSA

Obstructive sleep apnea

PD

Parkinson’s disease

RAGE

Receptor for advanced glycation end products

ROS

Reactive oxygen species

SAS

Sleep apnea syndrome

TGF-β

Transforming growth factor beta

TNF-α

Tumor necrosis factor-alpha

TNFR

Tumor necrosis factor receptor

TRADD

TNF receptor-associated death domain

8-oxodG

8-Oxo-2′-deoxyguanosine

Introduction

Researchers have increasingly shown that the greatest known risk factor for Alzheimer’s disease (AD) is advancing age (Bracco et al. 1994; Corkin et al. 1983; Ptok et al. 2000; Sando et al. 2008; Sonobe et al. 2010). Most individuals with AD are age 65 and older (Koukolik 1986; Obermayr et al. 2003). One of the greatest mysteries of AD is why risk rises so dramatically with aging.

Telomeres are a DNA sequence that appears at the end of each chromosome. The telomeres get shorter and shorter as cells divide (Tsuji et al. 2002). When a cell stops replicating, it enters into a period of decline known as “cell senescence,” which is the cellular equivalent of aging (Gupta et al. 2007; Riou et al. 2002; Tsolou et al. 2008; Zhou et al. 2006). Compelling studies have shown that the steady shortening of telomeres with each replication in cells plays an important role in senescence via oxidative stress and inflammation (Al-Attas et al. 2010; Furumoto et al. 1998; Masi et al. 2011; Melk et al. 2003; Takasaki et al. 2003; Tanaka et al. 2007; Tsuji et al. 2002). A number of articles have documented telomere shortening in diseases of aging (Chen et al. 2011; Melk et al. 2000; Ren et al. 2009), including AD (Zhang et al. 2003).

This review is focused on the role of telomere shortening in the pathogenesis of AD involved in oxidative stress and inflammation (Fig. 1). We will discuss how telomere shortening is associated with AD pathologies. That telomere shortening plays an important role in cognitive impairment of AD will also be discussed. An overview will be provided for the proposed general pathogenic mechanism of telomere shortening in AD. Finally, we will discuss an effective measure to inhibit telomere shortening as a very attractive drug target for AD.
https://static-content.springer.com/image/art%3A10.1007%2Fs12017-012-8207-9/MediaObjects/12017_2012_8207_Fig1_HTML.gif
Fig. 1

Potential roles of telomere shortening in the pathogenesis of AD. Roles of telomere shortening in cognitive impairment in AD are still unclear, as telomere shortening may contribute to cognitive impairment in human AD patients, but improve cognitive impairment in transgenic AD model mice (A). As for Aβ production, telomere shortening may decrease Aβ production and rescue amyloid plaques in a transgenic mice AD model where there are no reports about the role of telomere shortening in Aβ production in human AD patients (B). There is no evidence indicating the effects of telomere shortening on tau-related pathology (C) and apoptosis and neuronal injury and death in AD (D)

Telomeres

Telomeres are sequences of DNA chains of chemical code at the end of a chromosome, made of four nucleic acid bases: G for guanine, A for adenine, T for thymine and C for cytosine as other DNA (Aguade et al. 1994; Brown et al. 1990; Levy et al. 1992). The word telomere derives from the Greek word: telos meaning “end” and merοs meaning “part” (Boukamp and Mirancea 2007; Jain and Cooper 2010; Kipling and Cooke 1992). Telomeres are made of repeating sequences of TTAGGG on one strand of DNA bound to AATCCC on the other strand (Gaynutdinov et al. 2009; Reeve et al. 1993).

The main function of telomeres is to protect the end of the chromosome from deterioration or from fusion with neighboring chromosomes (Gisselsson et al. 2001; Qi et al. 2005; Sawyer et al. 1994). Telomeres play important roles in genomic replication, repair and maintenance machinery (Grandin and Charbonneau 2008; Peng and Lin 2009; Rampazzo et al. 2010; Viscardi et al. 2005).

Telomere Shortening

Telomeres are accountable for the programming of genetic information and the consistency of the information held in chromosomes through the cell division process (Allsopp et al. 1995; Crossen et al. 1993; Vodenicharov and Wellinger 2007). It was thought that the telomeres get shorter each time as cells divide. Telomeres are depleted, and “real DNA” information is lost after approximately 50–70 cell divisions in humans (Chawla et al. 2011; Starr et al. 2008; Zvereva et al. 2010). An increasing amount of literature has noted that telomere shortening is associated with cell division in vitro and in vivo (Allsopp et al. 1995; Bayne et al. 2011; Kajstura et al. 2000; Kveiborg et al. 1999; Rajaraman et al. 2007; Uziel et al. 2010). Eventually, cells can no longer reproduce, and they age and die.

It is well accepted that telomere shortening has been closely related to the pathogenesis of diseases, including cancers (Martinez-Delgado et al. 2011; Mu et al. 2012; Takagi et al. 2000), dementia (Jenkins et al. 2006; Panossian et al. 2003; Rolyan et al. 2011), hypertension (Farrag et al. 2011), diabetes mellitus (Olivieri et al. 2009; Zee et al. 2010a), cardiovascular diseases (Epel et al. 2009; Satoh et al. 2008), dyskeratosis congenital (Vulliamy et al. 2004), ulcerative colitis (Kinouchi et al. 1998; O’Sullivan et al. 2002), atherosclerosis (Nowak et al. 2002; Samani et al. 2001), and metabolic syndrome (Obana et al. 2003; Yamada 2003).

However, the role of telomere length is far from being understood now. Research studies have documented lack of telomere length shortening during aging and cancers (Broccoli et al. 1996; Gilley and Blackburn 1994; Kang et al. 2003). It seems that there is much more variation in the behavior of telomere length than initially believed (Halaschek-Wiener et al. 2008; Hosgood et al. 2009; Mirabello et al. 2010, 2011; Polychronopoulou and Koutroumba 2004; Thomas et al. 2008).

Telomere and Neurodegeneration

Neurodegeneration, an umbrella term for the progressive loss of structure or function of neurons, is a common theme of many nervous system diseases, such as AD (Crews and Masliah 2010), Parkinson’s disease (PD) (Maeda et al. 2009), Huntington’s disease (HD) (Bates et al. 1990; Gilliam et al. 1987; Landegent et al. 1986), epilepsy(Brandt et al. 1993; Garcia-Cruz et al. 2000) and stroke (von Zglinicki et al. 2000; Zee et al. 2010b). Neurodegenerative disorders are among the most common to affect us with aging. Neurodegeneration can occur in the different levels of maintenance and plasticity of neural circuitry in the mature nervous from molecular to systemic (Crews and Masliah 2010; Mattson 1990, 1992; Nothias et al. 1991).

A growing body of literature shows that telomeres have been involved in the process of neurodegeneration and neurodegeneration diseases (Flanary et al. 2007; Hamet and Tremblay 2003; Jaskelioff et al. 2011). Telomere length is associated with cognitive decline in elders, and telomere length may serve as a biomarker for cognitive aging (Devore et al. 2011; Insel et al. 2012; Kljajevic 2011; Martin-Ruiz et al. 2006; Yaffe et al. 2011). Telomere shortening is a marker of cellular aging and has been associated with dementia risk of AD (Grodstein et al. 2008; Jenkins et al. 2008).

Short telomere length is associated with high oxidative stress and various age-related diseases, including PD. Several research studies have noted that telomere shortening is involved in the pathogenesis of PD, an age-related disease (Guan et al. 2008; Tomac and Hoffer 2001). In PD patients, it seemed that telomere shortening was dependent on plasmatic concentrations of carbonyl proteins (Watfa et al. 2011). Guan et al. found a significant PD-associated decrease in telomeres ranging in length from 23.1 to 9.4 kb in patients in their 50 and 60 s (Guan et al. 2008). These observations suggest that telomere shortening is accelerated in PD patients. Some research documents have indicated that HD genes are closely linked with telomeres (Cheng et al. 1989; Gusella et al. 1986; Landegent et al. 1986; Theilmann et al. 1989). Genetic linkage studies have shown the HD mutation to the distal region of the short arm of human chromosome 4 (Pritchard et al. 1990). The HD gene is located in a very small physical region at the tip of the chromosome, bordered by D4S10 and the telomere (Gilliam et al. 1987). The HD locus is most likely within 325 kilobases of the chromosome 4p telomere (Doggett et al. 1989). Evidence from family studies showed that the gene causing HD is telomeric to D4S95 and D4S90 which are in significant linkage with HD gene (Pritchard et al. 1990; Robbins et al. 1989).

Accumulating evidence has correlated short telomeres with age-related disorders, including myocardial infarction, atherosclerosis, and stroke (Collerton et al. 2007; Martin-Ruiz et al. 2006; Wong et al. 2010; Zee et al. 2010b). Telomere length shortening is a potential risk predictor for vascular diseases, including stroke (Zee et al. 2010b). Telomere length may predict mortality, dementia, and cognitive decline after stroke (Martin-Ruiz et al. 2006). The greater the baseline telomere length is, the lower the risks for dementia and cognitive decline, and death. Telomere length may also be an independent predictor of the risk for vascular dementia (von Zglinicki et al. 2000). In addition, telomere-associated candidate genes represent potential risk predictors for stroke, including TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP and TERC (Zee et al. 2011). Deficiency of telomerase activity aggravates the blood brain barrier disruption and neuroinflammatory responses in a model of experimental stroke (Zhang et al. 2010). Furthermore, short telomere length contributes to the pathogenesis of several stroke-related disorders, including cardiovascular diseases, obesity, hypertension, atherosclerosis and diabetes (Diaz et al. 2010a, b; Fitzpatrick et al. 2011; van der Harst et al. 2008, 2010; Willeit et al. 2010). A number of articles have noted that short telomere length is a marker for cardiovascular diseases (Zee et al. 2011). Short leukocyte telomere length is associated with cardiovascular risk factors and diseases as well as type 2 diabetes, and is a predictor of cardiovascular disease in elderly patients with hypertension (Fyhrquist et al. 2011). Shorter telomeres have been associated with coronary artery calcification, a validated indicator of coronary atherosclerosis (Diaz et al. 2010a; Mainous et al. 2010). That telomere shortening is involved in the various stages of atherosclerosis implicates preferential involvement in advanced vessel pathology and acute vascular syndromes (Willeit et al. 2010).

Telomere Shortening and AD

Telomere shortening has been documented in the linking with the pathogenesis of AD by research studies from AD patients and in in vivo and in vitro models (D’Introno et al. 2006; Guan et al. 2012; Majores et al. 2000; Panossian et al. 2003; Silva et al. 2008; Thomas and Fenech 2007) (Fig. 1). Telomere shortening may be hastened by the factors of oxidative stress, inflammatory elements, lifestyle practice, excess stress, and any other factors which contribute to the AD process (D’Introno et al. 2006; Damjanovic et al. 2007; Jenkins et al. 2008; Kruk et al. 1995; Panossian et al. 2003; Thomas and Fenech 2007; Zhang et al. 2003). In 2000, it was found that the 234-bp allele of the D10S1423 marker on chromosome 10p12-14 (40 cM from the telomere) is an allelic association with an increased AD risk and provides further evidence for an AD susceptibility locus on chromosome 10 (Majores et al. 2000). Chronic stress is associated with altered T-cell function and accelerated immune cell aging as suggested by excessive telomere loss (Damjanovic et al. 2007). Research documents reported that T-cell telomere length inversely correlated with serum levels of the pro-inflammatory cytokine TNF-α, with the proportion of CD8+ T cells lacking the expression of the CD28 co-stimulatory molecule, and with apoptosis in AD patients (Panossian et al. 2003). These findings suggest that telomere shortening in T cells correlates with AD status, also indicating an immune involvement in AD pathogenesis (Panossian et al. 2003). Elevated telomerase activity of phytohemagglutinin-activated lymphocytes showed an accelerated telomere dysfunction in lymphocytes of AD patients, which decreases the proliferation activity of lymphocytes, and subsequently results in the impairment of immune function in AD patients (Zhang et al. 2003). In addition, increased absence of telomeres may indicate AD/dementia status in older individuals with Down syndrome (Jenkins et al. 2008), and cerebellum telomere lengths were directly correlated in individuals with AD (Lukens et al. 2009).

Advanced age and presence of intra-cerebral Aβ deposits are known to be major risk factors for the development of neurodegeneration in AD (Flanary et al. 2007). Aβ generation and deposition is recognized as the triggering mechanism of AD (Finder 2010; Sisodia and Price 1995). The Aβ hypothesis dominates the field of scientific research and provided the intellectual framework for therapeutic intervention for AD (Fiala and Veerhuis 2010; Pimplikar 2009). Flanary et al. (2007) noted that microglial cells exhibit significant telomere shortening and reduction in telomerase activity with normally aging rats and that in humans, there is a tendency toward telomere shortening with the presence of dementia. Microglial cell senescence associated with telomere shortening and normal aging is exacerbated by the presence of Aβ. They suggest that telomere shortening contributes to degeneration of microglia as a factor in the pathogenesis of AD (Flanary et al. 2007). However, recent research demonstrated that telomere shortening reduces amyloid pathology through decreasing the activation of microglia in aging APP23 transgenic mice, a mouse model for AD (Rolyan et al. 2011). Telomere shortening improves cognitive impairment and reduces the progression of amyloid pathology in aging APP23 transgenic mice (Rolyan et al. 2011). The same research also noted telomere shortening is associated with the accumulation of DNA damage foci and loss of neurons in the aging brain. Telomere shortening also reduces adult dentate gyrus neurogenesis and impairs the maintenance of post-mitotic neurons in aged late generation telomerase-deficient mice (Rolyan et al. 2011). Does telomere length reflect brain telomere length? What is the role of telomere length in AD pathogenesis? The very mechanism is yet unclear about the role of telomere length in AD pathogenesis.

Oxidative Stress: A Direct Mediator of Telomere Shortening in AD?

Oxidative stress plays an essential role in AD pathogenesis by the function of linking agent (Clark et al. 2010; Herring et al. 2010; Resende et al. 2008). Oxidative-induced telomere DNA damage is an important determinant of telomere shortening (Jennings et al. 2000; Kawanishi and Oikawa 2004; Liu et al. 2003). Telomere shortening has also been accelerated by oxidative stress (Proctor and Kirkwood 2002; Serra et al. 2000). Hence, the hypothesis has been made that oxidative-mediated telomere shortening contributes to AD pathogenesis (Fig. 1).

Oxidative Stress in AD

Oxidative stress is an early feature of AD pathology and has been proposed to be an important factor in the pathogenesis of AD (Aluise et al. 2010; Butterfield 2011; Gibson et al. 1999; Pallas et al. 2008; Singh et al. 2010). Over the past decade, extensive oxidative research has been performed on the pathogenesis of AD (Ansari and Scheff 2010; Gella and Durany 2009; Gibson et al. 1999; Srikanth et al. 2011; Wan et al. 2011). An important feature of the hypothesis of AD is that oxidative stress may trigger an active, self-perpetuating cycle of chronic neuroinflammation which serves to further promote oxidative stress and may contribute to irreversible neuronal dysfunction and cell death (Maccioni et al. 2009; Mhatre et al. 2004). Various researches have also evidenced that the interaction between oxidative stress and neuroinflammation leads to Aβ generation (Bonda et al. 2010; Christen 2000). Oxidative stress has been proposed to be an important factor in the pathogenesis of AD and to contribute to Aβ generation and the formation of NFT (Aliev 2011; Butterfield and Boyd-Kimball 2004; Christen 2000; Zhu et al. 2007). Research studies reported that interaction between oxidative stress and neuroinflammation leads to Aβ generation (Simpson et al. 2010; Yao et al. 2004). An interaction between chemokine and oxidative stress has been reported which infers that the disturbed system of chemokine induced by oxidative stress is a main cause of Aβ generation (Aukrust et al. 2001; Cuschieri and Maier 2007). Neuroinflammation can be a cause and a consequence of chronic oxidative stress. Enhanced inflammation may generate copious amounts of reactive oxygen and reactive nitrogen species in ambient neurons (Apelt et al. 2004; Mhatre et al. 2004). There are many data that revealed that neuroinflammation-induced oxidative stress increases the expression of Aβ (Aliev 2011; Candore et al. 2010; Simpson et al. 2010). Aβ generation requires two sequential cleavages of the APP by two proteolytic enzymes β-secretase and γ-secretase. Oxidative damage up-regulates Aβ via inducing the activity of β- and γ-secretase (Apelt et al. 2004; Cai et al. 2011; Tamagno et al. 2008; Zhiyou et al. 2009). In addition, intracellular Aβ accumulation promotes a significant oxidative and inflammatory mechanism that generates a vicious cycle of Aβ generation and oxidation, each accelerating the other (Bayer et al. 2006; Misonou et al. 2000; Smith et al. 1998; Standridge 2006).

Oxidative Stress and Telomere Shortening

The telomere is a promising genetic biomarker for oxidative stress and reflects the cumulative amount of oxidative damage to the organism (Cattan et al. 2008; Ozsarlak-Sozer et al. 2011; Saretzki et al. 2003; Saretzki and von Zglinicki 1999; Sekoguchi et al. 2007; Serra et al. 2000; Shen et al. 2009; Shlush et al. 2011; Tarry-Adkins et al. 2008; von Zglinicki 2000; Watfa et al. 2011; Zhang and Ju 2010). Substantial studies noted that telomere shortening during human aging has been induced and accelerated by oxidative stress (Jennings et al. 2000; Oikawa and Kawanishi 1999; Sebastian et al. 2009; Sozou and Kirkwood 2001; Tchirkov and Lansdorp 2003). Telomere shortening may progress in proportion to lifetime depression exposure, including oxidative stress (Kurz et al. 2004; Tanaka et al. 2007; Wolkowitz et al. 2011). Oxidant agents can induce premature senescence and accelerate telomere shortening and reduce telomerase activity (Matthews et al. 2006). Age-dependent telomere shortening can be decelerated by the suppression of intracellular oxidative stress and/or by telomerase retention by enrichment of intracellular vitamin C (Furumoto et al. 1998). It is also evidenced that the site-specific DNA damage at the GGG sequence by oxidative stress may play an important role in increasing the rate of telomere shortening with aging (Oikawa and Kawanishi 1999). Free G-rich telomeric single strands are a strong inductor of the p53 pathway, and exposure of oxidative stress seems to be the first step in the signal transduction cascade to telomere shortening (von Zglinicki 2000). Telomeres, special structures located in the extremes of chromosomes, are susceptible to oxidative damage (Bunout and Cambiazo 1999). A T-loop telomere structure, leading to the accumulation of basic sites and single-strand breaks, contributes to the sensitivity of telomeres to oxidative damage and telomere shortening (Bar-Or et al. 2001; von Zglinicki 2000). It has also been shown that oxidative stress plays a major role in determining the rate of loss of telomere DNA (Proctor and Kirkwood 2002). Additional research has noted that oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability and apoptosis (Liu et al. 2003). Kawanishi and Oikawa demonstrated that the formation of 8-oxodG at the GGG triplet in telomere sequence (5′-TTAGGG-3′) induced by oxidative stress may promote the acceleration of telomere shortening (Kawanishi and Oikawa 2004).

Telomere shortening is associated with the pathogenesis of many diseases which are involved in oxidative stress, such as AD, diabetes, major depression, cancers, hypertension, obesity and cardiovascular diseases (Table 1). Recent research demonstrated that telomere shortening may progress in proportion to lifetime depression exposure and does not antedate depression via increased peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) (Wolkowitz et al. 2011). It was evidenced that oxidative stress induces telomere genomic instability, telomere shortening, replicative senescence and dysfunction of chondrocytes in osteoarthritis cartilage (Yudoh et al. 2005). A research study noted that insulin resistance and oxidative stress, implicated both in the biology of aging and in aging-related disorders, are associated with accelerated telomere shortening in leukocytes (Demissie et al. 2006). It was confirmed that monocyte telomere shortening in type 2 diabetes may be due to increased oxidative DNA damage to monocyte precursors during cell division (Sampson et al. 2006). In diabetes, the mechanisms of telomere shortening include increased oxidative DNA damage (Kejariwal et al. 2008), mitochondrial production of reactive oxygen species (Salpea et al. 2010) and the damage from malondialdehyde peroxidation (Murillo-Ortiz et al. 2012). Herbert et al. (2008) demonstrated that angiotensin II-mediated oxidative DNA damage accelerates cellular senescence in cultured human vascular smooth muscle cells which is associated with accelerated telomere attrition. Metabolic syndrome has been linked to increased oxidative DNA damage and telomere shortening (Salpea et al. 2010; Satoh et al. 2008). The study completed by Satoh et al. indicated that telomere shortening of endothelial progenitor cells through increased oxidative DNA damage may play an important role in the pathogenesis of coronary artery disease (Satoh et al. 2008). Recent research evidenced that telomeres are susceptible to cigarette smoke-induced oxidative damage and chromosomal instability of mouse embryos in vitro (Huang et al. 2010). Telomere-dependent senescent phenotype of lens epithelial cells as a biological marker of aging and cataractogenesis is due to the role of oxidative stress intensity and specific mechanism of phospholipid hydroperoxide toxicity in lens and aqueous (Babizhayev et al. 2011b). Telomere shortening, correlated with the oxidative stress and severity of disease, is associated with a diagnosis of periodontitis (Masi et al. 2011). Additional research studies demonstrated that telomere shortening is involved in the process of cancer via susceptibility genotypes of metabolizing and DNA-repairing genes by oxidative damage (Broberg et al. 2005), increased 5-F(2t)-IsoP and 8-oxodG oxidative biomarkers (Shen et al. 2009) and increased oxidative DNA damage (Widmann et al. 2007). Collectively, these data suggest oxidative-mediated telomere DNA damage as an important determinant of telomere shortening (Babizhayev et al. 2011a; Houben et al. 2008; Richter and von Zglinicki 2007; Starr et al. 2008; Watfa et al. 2011).
Table 1

Oxidative stress and telomere shortening

Diseases

Samples

Telomere length

Possible inflammation mechanism

References

AD

Human T lymphocytes

Shortened

N/A

Jenkins et al. (2008)

Human T cells, B cells and monocytes

Shortened (T cells)

Lacking expression of the CD28 costimulatory molecule

Panossian et al. (2003)

Aging

Mouse granulosa cells and ovarian

Shortened

Estrogen deficiency

Bayne et al. (2011)

Human blood

Shortened

Increased IL-6 and TNF-α levels

Kiecolt-Glaser et al. (2011)

Human blood leukocytes

Shortened

N/A

Chen et al. (2011)

Human liver tissues

Shortened

Chronic inflammation

Aikata et al. (2000)

Rheumatoid arthritis

Human blood leukocytes

Shortened

Elevated CD53, which results from the increased oxidative stress

Pedersen-Lane et al. (2007)

Anemia

In vitro

Shortened

H2O2 damage and p53 up-regulation

Uziel et al. (2008)

Atherosclerosis

In vitro and in vivo

Shortened

Increased oxidative DNA damage

Matthews et al. (2006)

CADASIL

Human blood leukocytes

Shortened

Systemic oxidative stress

Ragno et al. (2011)

Cancer

Human blood leukocytes

Shortened

Increased 5-F(2t)-IsoP and 8-oxodG oxidative biomarkers

Shen et al. (2009)

Human blood leukocytes

Shortened

Increased oxidative stress

Widmann et al. (2007)

Human bladder cancer tissue

Shortened

Susceptibility genotypes of metabolizing and DNA-repairing genes

Broberg et al. (2005)

Human colorectal tumor tissue

Shortened

Oxidative stress by the lack of quinone oxidoreductase activity

Takagi et al. (2002)

Human prostate tumor tissue

Shortened

Early somatic DNA alteration

Meeker et al. (2002)

COPD

Human blood leukocytes

Shortened

Elevated plasma levels of various cytokines, interleukin-6

Savale et al. (2009)

In vivo and in vitro

Shortened

Elevated MCP-1, IL-8 and ICAM-1 levels

Amsellem et al. (2011)

Human blood leukocytes

Shortened

IL-6 correlating negatively with telomere length

Savale et al. (2009)

CVD

Human blood leukocytes

Shortened

Increased oxidative DNA damage

Satoh et al. (2009)

Human blood endothelial cells

Shortened

Increased oxidative DNA damage

Satoh et al. (2008)

Human blood endothelial cells

Shortened

Increase in lipid peroxidation and caveolin-1 gene expression, and loss of eNOS expression and increase in Cox-2 mRNA, lower TRF1 protein level

Voghel et al. (2007)

Depression

Human blood leukocytes

Shortened

Increased peripheral markers of oxidation (F2-isoprostane/vitamin C ratio)

Wolkowitz et al. (2012)

Diabetes

Human blood leukocytes

Shortened

Malondialdehyde peroxidation and adiponectin

Murillo-Ortiz et al. (2012)

Human blood leukocytes

Shortened

Mitochondrial production of reactive oxygen species

Salpea et al. (2010)

Human colonic mucosal cells

Shortened

Increased oxidative DNA damage

Kejariwal et al. (2008)

Human blood leukocytes

Shortened

Impaired glucose tolerance, increased thiobarbituric acid reactive substances

Adaikalakoteswari et al. (2007)

Human blood leukocytes

Shortened

Impaired glucose tolerance

Adaikalakoteswari et al. (2005)

Human blood monocytes

Shortened

Increased oxidative DNA damage

Sampson et al. (2006)

Dyskeratosis congenita

In vivo (a mouse model)

Shortened

Reactive oxygen species increase

Gu et al. (2011)

Hypertension

Human blood leukocytes

Shortened

Impaired zinc homeostasis and inflammation

Cipriano et al. (2009)

Human blood leukocytes

Shortened

A higher renin-to-aldosterone ratio

Vasan et al. (2008)

Liver diseases

Human biopsy liver samples

Shortened

p21 up-regulation

Nakajima et al. (2010)

MDS

Human blood leukocytes and in vitro

Shortened

Involving TNF-α and IL-32

Marcondes et al. (2009)

Obesity

Human blood leukocytes

Shortened

Disturbed mitochondrial function was associated with signs of increased oxidative stress (protein carbonyl content, 8-hydroxy-2′-deoxyguanosine)

Niemann et al. (2011)

OSA

Human blood leukocytes

Shortened

Increased myeloid-related protein 8/14 and decreased catestatin

Kim et al. (2010)

Osteoporosis

Human blood leukocytes

No change

N/A

Sanders et al. (2009)

Human blood leukocytes

Shortened

Oxidative stress and low-level chronic inflammation

Zhai et al. (2006)

Parkinson’s disease

Human blood leukocytes

No change

Telomere shortening was mainly dependent on plasmatic concentrations of carbonyl proteins

Watfa et al. (2011)

Human blood leukocytes

No change

N/A

Hudson et al. (2011)

Human blood leukocytes

Shortened

N/A

Guan et al. (2008)

Rheumatoid arthritis

Human blood

Shortened

Systemic inflammation, immune-senescence

Costenbader et al. (2011), Steer et al. (2007)

Human blood

Shortened

Immune abnormalities and telomerase insufficiency

Fujii et al. (2009)

Human blood

Shortened

Elevated CD53 from the increased oxidative stress

Pedersen-Lane et al. (2007)

SAS

Human blood leukocytes

Shortened

Metabolic alterations

 

Ulcerative colitis

Human blood leukocytes

Shortened

Increased phosphorylation of histone H2AX (gammaH2AX), a DNA damage signal

Risques et al. (2008)

Human rectal fibroblasts

Long

Decreased superoxide dismutase

Getliffe et al. (2006)

Human mucosa

Shortened

Chromosomal instability

O’Sullivan et al. (2002)

AD Alzheimer’s disease, CADASIL cerebral autosomal dominant arteriopathy and leukoencephalopathy, COPD chronic obstructive pulmonary disease, Cox-2 cyclooxygenase 2, CVD cardiovascular disease, eNOS endothelial nitric oxide synthase, ICAM-1 inter-cellular adhesion molecule 1, IL interleukin, MCP-1 macrophage chemoattractant protein 1, MDS myelodysplastic syndromes, OSA obstructive sleep apnea, TNF-α tumor necrosis factor-alpha

Oxidative Stress: A Direct Mediator of Telomere Shortening in AD?

A number of literature evidenced that telomere shortening, a marker for a person’s ability to withstand oxidative stress, has a close link with AD pathogenesis. Thus, oxidative stress through inducing telomere shortening contributes to AD, including cognitive impairment and pathology (Devore et al. 2011; Grodstein et al. 2008; Harris et al. 2012; Lukens et al. 2009; Valdes et al. 2010; Zekry et al. 2010a). Genomic instability resulting from telomere loss may increase gene over-expression as a result of gene amplification, through the repeated breakage and fusion of chromosomes through the breakage/fusion/bridge (BFB) cycle (Cheung and Deng 2008; Murnane 2006; Pelliccia et al. 2010; Thomas and Fenech 2007; Vukovic et al. 2007). Therefore, it may be possible that oxidative-mediated telomere shortening may be more susceptible to BFB cycles and lead to over-expression of Alzheimer’s-related genes such as tau, ApoE and APP (Honig et al. 2006; Rolyan et al. 2011; Tanzi et al. 1988, 1992; Thomas and Fenech 2007; Wikgren et al. 2012; Zekry et al. 2010a). However, the mechanism of the exact role of telomere shortening mediated by oxidative damage in the pathogenesis of AD is not well clarified. Is telomere shortening is a cause or consequence of oxidative stress in AD? What is the concrete relationship between oxidative-mediated telomere shortening and AD pathology? What is the exact mechanism of cognitive impairment resulting in telomere shortening induced by oxidative stress?

Inflammation: An Inducer of Telomere Shortening in AD?

Neuroinflammation plays a prominent role in the progression of AD and may be responsible for degeneration in vulnerable regions such as the hippocampus (Rosi et al. 2004; Wang et al. 2011a). Increasing research studies have also shown that neuroinflammation leads to Aβ generation and tau hyper-phosphorylation (Agostinho et al. 2010; Candore et al. 2010; Koistinaho et al. 2011; Yao et al. 2004). Compelling literature has demonstrated that inflammation plays an important role in telomere shortening, including aging, cardiovascular disease, dementia, metabolic syndrome and neurodegenerative diseases (Aikata et al. 2000; Aviv 2004; Ilmonen et al. 2008; Teyssier et al. 2010). Accordingly, inflammation may induce telomere shortening which is involved in the process of neurodegeneration to AD (Fig. 1).

The Hypothesis of Inflammation in AD

Emerging research studies over the past decade have demonstrated that inflammation plays an important role in the pathogenesis of AD (Jia et al. 2005; Marchesi 2011; Viel and Buck 2011). Clinical research studies have shown that systemic inflammation leads to increased cognitive decline and exaggerated sickness behavior in AD (Guerreiro et al. 2007; Holmes and Butchart 2011). Inflammatory components related to AD neuroinflammation include inflammatory cytokines (Berkenbosch et al. 1992; Guerreiro et al. 2007), chemokines (Huerta et al. 2004; Naert and Rivest 2011; Reale et al. 2008), activated microglia and astrocytes (Cameron and Landreth 2010; Peters et al. 2009; Vijayan et al. 1991), the complement system (Bergamaschini et al. 2001; Ricchieri et al. 1983; Town 2010), as well as oxidative agents (Butterfield and Lauderback 2002; Ferretti et al. 2012; Tuppo and Forman 2001).

Neuroinflammation may be a cause and a consequence of chronic oxidative stress (Andersen 2004; Efendic et al. 1999). Oxidants can stimulate proinflammatory gene transcription in microglia and astrocytes, leading to various inflammatory reactions. Enhanced inflammation may generate copious amounts of reactive oxygen and reactive nitrogen species in ambient neurons (Apelt et al. 2004; Martinez 2006; Mhatre et al. 2004). There are many data that revealed that neuroinflammation-induced oxidative stress increases expression of Aβ and tau hyper-phosphorylation (Ayasolla et al. 2004; Butterfield et al. 2002; Candore et al. 2010; von Bernhardi 2007; Zhu et al. 2000). An important feature of the hypothesis of AD is that oxidative stress may trigger an active, self-perpetuating cycle of chronic neuroinflammation which serves to further promote oxidative stress and may contribute to irreversible neuronal dysfunction and cell death (Candore et al. 2010; Maccioni et al. 2009; Mhatre et al. 2004; Yao et al. 2004). Many research studies also evidenced that interaction between oxidative stress and neuroinflammation leads to Aβ generation and tau hyper-phosphorylation (Agostinho et al. 2010; Candore et al. 2010; Yao et al. 2004; Zhu et al. 2000). Therefore, inflammation is important in the pathogenic cascade of neurodegeneration in AD, suggesting that chronic inflammation in AD offers therapeutic opportunities.

There are also a number of reports that have indicating that neuroinflammation contributes to the pathogenesis of AD such as inflammation-mediated apoptosis (Calissano et al. 2009; Canu and Calissano 2003; McPhie et al. 2003), decreased Aβ clearance through the blood brain barrier induced by chronic neuroinflammation and regulated by LRP-1 and RAGE (Deane et al. 2004; Donahue et al. 2006; Jeynes and Provias 2008; Yan et al. 2008), as well as neuroinflammation triggered by Aβ or tau hyper-phosphorylation (Butterfield and Boyd-Kimball 2004; Butterfield et al. 2007, 2010; Flirski and Sobow 2005; Lecanu et al. 2006; Metcalfe and Figueiredo-Pereira 2010; Yatin et al. 1999).

Inflammation and Telomere Shortening

Telomere shortening may be related to diseases of aging and neurodegeneration involving inflammation (Amsellem et al. 2011; Fitzpatrick et al. 2007; Nawrot and Staessen 2008; Richards et al. 2008; Thorsteinsdottir et al. 2011) (Table 2). Telomere shortening often occurs with repeated mitoses in response to oxidation and inflammation (Wolkowitz et al. 2011).
Table 2

Inflammation and telomere shortening

Diseases

Samples

Telomere length

Possible inflammation mechanism

References

AD

In vivo (mice)

Shortened

Decreased reactive microgliosis

Rolyan et al. (2011)

Aging

Human blood

Shortened

Inflammation factors induced by oxidative stress

Martin-Ruiz et al. (2011)

Human blood

Shortened

Elevated IL-6 and TNF-α levels

Kaszubowska et al. (2011)

In vitro (human glomerular mesangial cells

Shortened

Elevated expression of p53 and p21 as an inflammation mediator

Feng et al. (2011)

Human blood

Shortened

Elevated IL-6 and TNF-α levels

Kiecolt-Glaser et al. (2011)

Human blood leukocytes

Shortened

N/A

Chen et al. (2011)

Human liver tissues

Shortened

Chronic inflammation

Aikata et al. (2000)

Human blood leukocytes

Shortened

Oxidative stress-dependent inflammation

Valdes et al. (2005)

Anemia

Human blood

Shortened

N/A

den Elzen and Gussekloo (2011)

Atherosclerosis

In vitro model (CD14(+) CD16(+) monocytes

Shortened

Inducing expression of CD209 (chemokine receptors), release of cytokines

Merino et al. (2011)

Human blood leukocytes

Shortened

N/A

Ilmonen et al. (2008), Nettleton et al. (2008)

Barrett’s esophagus

Human blood leukocytes

Shortened

N/A

Risques et al. (2007)

CADASIL

Human blood leukocytes

Shortened

Oxidative stress-dependent inflammation

Ragno et al. (2011)

Colorectal cancer

Human blood leukocytes

Shortened

Lower level of fetuin-A (a circulating calcium-regulatory glycoprotein that inhibits vascular calcification and associated with inflammation and outcome)

Maxwell et al. (2011)

COPD

In vivo and in vitro

Shortened

Elevated MCP-1, IL-8, and ICAM-1 levels

Amsellem et al. (2011)

Human blood leukocytes

Shortened

IL-6 correlating negatively with telomere length

Savale et al. 2009)

Human blood leukocytes

Shortened

Elevated levels of inflammatory markers (CRP, sTNF receptors)

Houben et al. (2009)

Crohn disease

Human ileal mucosa

Longer

CD28 molecule by activated resident lymphocytes

Meresse et al. (2001)

CVD

Human blood leukocytes

Shortened

Elevated IL-6 and immunosenescence

Shiels et al. (2011), Spyridopoulos et al. (2009)

Human blood leukocytes

Shortened

Increased CRP and homocysteine levels

Richards et al. (2008)

Human blood leukocytes

Shortened

Elevated IL-6 and CRP

Bekaert et al. (2007)

In vitro (human coronary artery endothelial cells)

Shortened

Telomerase-based immortalization modifies the angiogenic/inflammatory responses

Baumer et al. (2011)

Dementia

Human blood leukocytes

Shortened

Oxidative stress-dependent inflammation

Valdes et al. (2010)

Depression

Human biopsies

Shortened

Oxidative stress-dependent inflammation

Teyssier et al. (2010)

Human blood leukocytes

Shortened

Elevated IL-6

Wolkowitz et al. (2011)

Diabetes

Human blood

Shortened

Elevated IL-6

Shiels et al. (2011)

Human blood

Shortened

Elevated TNF-α and oxidative stress-dependent inflammation

Murillo-Ortiz et al. (2012)

Gastric cancer

Human blood leukocytes

Shortened

N/A

Hou et al. (2009)

Hepatocellular carcinoma

Human liver tissues

Shortened

Chronic inflammation

Isokawa et al. (1999)

Hypertension

Human blood leukocytes

Shortened

Impaired zinc homeostasis and inflammation

Cipriano et al. (2009)

Human blood leukocytes

Shortened

A higher renin-to-aldosterone ratio

Vasan et al. (2008)

Menopause

Human blood leukocytes

Shortened

Elevated CRP

Aviv et al. (2006)

Obesity

Human blood leukocytes

Shortened

Elevated TNF-α, CRP and active plasminogen activator inhibitor 1

Al-Attas et al. (2010)

OSA

Human blood leukocytes

Shortened

Increased myeloid-related protein 8/14 and decreased catestatin

Kim et al. (2010)

Osteoporosis

Human blood leukocytes

No change

N/A

Sanders et al. (2009)

Human blood leukocytes

Shortened

Oxidative stress and low-level chronic inflammation

Zhai et al. (2006)

Parkinson’s disease

Human blood leukocytes

No change

Oxidative stress-dependent inflammation

Eerola et al. (2010)

Periodontitis

Human blood leukocytes

Shortened

Reactive oxygen metabolites) and high sensitivity of CRP

Masi et al. (2011)

Rheumatoid arthritis

Human blood

Shortened

Systemic inflammation and immunosenescence

Costenbader et al. (2011), Steer et al. (2007)

Human blood

Shortened

Immune abnormalities and telomerase insufficiency

Fujii et al. (2009)

Human blood

Shortened

Elevated CD53 from the increased oxidative stress

Pedersen-Lane et al. (2007)

SAS

Human blood leukocytes

Shortened

Oxidative stress-dependent inflammation

Bhattacharjee et al. (2010)

Ulcerative colitis

Human biopsies

Shortened

Mutations in p53; increased p16 and p53 expression.

Thorsteinsdottir et al. (2011), Risques et al. (2011)

Human biopsies

Shortened

Increased gammaH2AX in colonocytes reflecting oxidative damage secondary to inflammation

Risques et al. (2008)

Human biopsies

Shortened

N/A

Kinouchi et al. (1998)

AD Alzheimer’s disease, CADASIL cerebral autosomal dominant arteriopathy and leukoencephalopathy, COPD chronic obstructive pulmonary disease, CRP C-reactive protein, CVD cardiovascular disease, ICAM-1 inter-cellular adhesion molecule 1, IL interleukin, OSA obstructive sleep apnea, SAS sleep apnea syndrome, TNF-α tumor necrosis factor-alpha

It is well known that leukocyte telomere shortening may predict early mortality and medical illnesses (Wang et al. 2011b; Wolkowitz et al. 2011). Leukocyte telomere shortening is a reliable marker of biological age, mortality risk and exposure to various pathological conditions, including cardiovascular disease, dementia, metabolic syndrome and infectious diseases (Aikata et al. 2000; Aviv 2004; Ilmonen et al. 2008; Teyssier et al. 2010). Leukocyte telomere length through chronic inflammation is positively associated with high-density lipoprotein cholesterol levels (Chen et al. 2009). Inflammation may induce rapid telomere shortening in peripheral blood leukocytes (Ragno et al. 2011). Leukocyte telomeres are shortened in major depressive disorder which is related to oxidation and inflammation (Wolkowitz et al. 2011). Leukocyte telomere length shortening is a potential risk predictor for cardiovascular disease, with increased arterial stiffness and cardiovascular burden via chronic inflammation (Wang et al. 2011b). As leukocyte telomere length is shaped by genetic, epigenetic and environmental determinants, Babizhayev and Yegorov (2011) evidenced that inflammation associated with tobacco smoking reduces leukocyte telomere length in a large population-based cohort under the effect of smoking duration. Leukocyte telomere shortening in relation to inflammation was associated with elevated TNF-α, CRP and active plasminogen activator inhibitor 1 among obese Arab youth (Al-Attas et al. 2010).

Lower socioeconomic status and various nutrients are relevant to accelerated biological aging and telomere length shortening, and predispose to early onset of disease through mechanisms that reflect their roles in cellular functions including inflammation, oxidative stress, DNA integrity, DNA methylation and telomerase activity (Bauer et al. 2009; Baumer et al. 2011; Paul 2011; Shiels et al. 2011). In addition, environmental and lifestyle factors may lead to telomere length shortening via oxidative stress and inflammation (Chan et al. 2010; De Meyer et al. 2008; Makino et al. 2009; Valdes et al. 2005). The rate of age-related telomere attrition was significantly associated with low relative income, housing tenure and poor diet (Shiels et al. 2011). Telomere attrition is a biomarker of the cumulative oxidative stress and inflammation induced by smoking and can serve as an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior (Babizhayev et al. 2011a; Mirabello et al. 2009).

Increasing documents have demonstrated that immune-senescence and systemic inflammation play an important role in telomere shortening (Costenbader et al. 2011; Georgin-Lavialle et al. 2010; Sloand et al. 2010; Teyssier et al. 2010). It has been found that telomere shortening occurs in the process of immune aging and chronic inflammatory disease (Andrews et al. 2010; Katepalli et al. 2008). Telomere length was inversely correlated to elevated circulating IL-6 and C-reactive protein (CRP), pro-inflammatory factors (Bekaert et al. 2007; Shiels et al. 2011). The progressive increase in inflammation and/or oxidative stress plays a direct role in telomere shortening with regard to inflammatory markers TNF-α, reactive oxygen metabolites and high sensitivity of CRP (Masi et al. 2011; Murillo-Ortiz et al. 2012). In CD14+CD16+ monocytes, increased inflammatory activity and ability to interact with endothelial cells contribute to telomere shortening via inducing the expression of CD209 (chemokine receptors) and release of cytokines (Merino et al. 2011). Lower levels of fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification and associated with inflammation and outcome, may be a contributing factor to telomere shortening in the pathogenesis of colorectal cancer (Maxwell et al. 2011). Telomere shortening was correlated with elevated levels of inflammatory markers (CRP, sTNF receptors) in chronic obstructive pulmonary disease (COPD) (Houben et al. 2009). There are many studies implicating that telomere shortening is triggered by elevated CD53 from increased oxidative stress (Pedersen-Lane et al. 2007), systemic inflammation (Costenbader et al. 2011; Steer et al. 2007), immune abnormalities and telomerase insufficiency in rheumatoid arthritis (Fujii et al. 2009).

Accelerated telomere attrition seems to be a main pathophysiology of cancer arising from chronic inflammation (DePinho and Wong 2003; Sastry and Parikh 2003; Young 2010). Chronic inflammation leads to telomere shortening in colorectal cancer through increasing the expression of p16 and p53 (Risques et al. 2011). Elevated expression of p53 and p21 seems to be the key mechanism involved in telomere shortening during aging (Feng et al. 2011).

It is well accepted that telomere biology maintenance impacts overall health status (Mirabello et al. 2009). Telomere length reflects cellular turnover and exposure to oxidative and inflammatory damage (Savale et al. 2009). Telomere shortening may reduce the capacity to respond to cellular stress occurring during inflammation. Telomere-mediated chromosomal instability triggers inflammation and death in mice through Toll-like receptor 4–induced NF-κB action and sensitizes cells to produce excess pro-inflammatory mediators (Bhattacharjee et al. 2010). Telomere dysfunction may induce inflammation in COPD, to which IL-6 was correlated negatively with telomere length (Amsellem et al. 2011; Savale et al. 2009).

Neuroinflammation: An Inducer of Telomere Shortening in AD?

Chronic neuroinflammation is a clear pathological hallmark of AD and be involved in cognitive impairment, Aβ generation and tau hyper-phosphorylation (Candore et al. 2010; Fiala and Veerhuis 2010; Golde 2002; Kamer 2010; van Exel et al. 2009). Telomere shortening has contributed to AD pathogenesis, including cognitive impairment and pathology. Neuroinflammation may be correlated with telomere shortening which participates in the process of neurodegeneration for AD (Paul 2011; Valdes et al. 2010; Zhang et al. 2003). An accelerated telomere dysfunction in lymphocytes of AD patients may increase telomerase activity and decrease proliferation activity of lymphocytes, and subsequently leads to the impairment of immune function (Zhang et al. 2003). Telomere shortening in T cells correlates with AD status, and T-cell telomere length also inversely correlates with serum levels of the pro-inflammatory cytokine TNF-α, with the proportion of CD8+ T cells lacking the expression of the CD28 co-stimulatory molecule, and with apoptosis (Panossian et al. 2003).

However, a recent in vivo study found that telomere shortening improves the spatial learning ability of aging APP23 transgenic mice (Rolyan et al. 2011). Telomere shortening, despite impairing adult neurogenesis and maintenance of post-mitotic neurons, reduces both amyloid plaque pathology and reactive microgliosis in APP23 transgenic mice. Thus, telomere shortening may inhibit the progression of amyloid plaque pathology through telomere-dependent effects on microglia activation (Rolyan et al. 2011).

Hence, further research is needed to determine the specific role of telomere shortening in the inflammatory process of AD. The same questions from the previous oxidative stress section apply here. Is telomere shortening a cause or consequence of inflammation in AD? What is the correlation between inflammation-mediated telomere shortening and AD pathology? What is the exact mechanism of cognitive impairment resulting in inflammation-dependent telomere shortening? Is the correlation between telomere shortening and inflammation a foe or friend of AD? Finally, is neuroinflammation a direct inducer of telomere shortening in AD?

Telomere Shortening and Cognitive Impairment in AD

Cognitive impairment is not caused by any one disease or condition (Johnson et al. 2005; Lee et al. 2010; Quadri et al. 2004; Ready et al. 2003). AD, the most common form of dementia, as well other dementias and conditions, such as stroke, traumatic brain injury, depression and developmental disabilities, can all cause cognitive impairment (Brown et al. 2011; Modrego and Ferrandez 2004; Talelli and Ellul 2004). Many factors contributes to the likely progression from mild cognitive impairment (MCI) to Alzheimer’s, including depression, hypertension, age, loss of ability to perform activities of daily living, cardiovascular diseases, stroke, diabetes and a low level of education (Craft et al. 2012; James et al. 2011; Li et al. 2011; Llano et al. 2011; Milwain and Nagy 2005; Palmer et al. 2007, 2008; Panza et al. 2007; Smith et al. 2010; van Rossum et al. 2010). A growing body of evidence suggests cognitive function may be maintained by preventing or controlling risk factors, such as high blood pressure, high cholesterol and diabetes (Anchisi et al. 2005; Bennett et al. 2005; Kim et al. 2002; Kume et al. 2010; Zhang et al. 2004). Additional data showed a significant connection that telomere shortening is a linear factor of cognitive impairment (Insel et al. 2012; Valdes et al. 2010). Leukocyte telomere length may be associated with cognitive performance in healthy women, suggesting a biomarker of cognitive aging in women before the onset of dementia (Valdes et al. 2010). Telomere length may be a prognostic marker for post-stroke cognitive decline, dementia and death (Martin-Ruiz et al. 2006).

Telomere shortening is linked with age-related pathologies including AD (Paul 2011). There is evidence that telomere shortening plays an important role in cognitive function in AD (Jenkins et al. 2008). Telomere shortening may increase the risk for developing MCI and may indicate AD dementia status in older individuals (Jenkins et al. 2008). Telomere length of T cells correlates with AD disease status, measured by Mini Mental Status Examination (MMSE) scores (Panossian et al. 2003).

There is a longitudinal study in very old patients indicating that telomere length is not used to distinguish between demented and non-demented patients, regardless of the type of dementia, or to predict dementia or MCI conversion, nor combined with the ApoE polymorphism (Zekry et al. 2010a, b). Telomere length is not associated with cognitive assessments and cognitive change, as both are particularly powerful markers of impending cognitive decline (Devore et al. 2011; Harris et al. 2006; Insel et al. 2012; Mather et al. 2010). Reduced telomere length in peripheral blood leukocytes in AD might not reflect reduced telomere length in bulk brain tissue (Lukens et al. 2009). A recent study also showed the contrary result that telomere shortening rescues both amyloid plaque pathology and inhibited microglia reactivation and improves the spatial learning ability of aging APP23 transgenic mice (Rolyan et al. 2011). The study showed that aged telomerase knockout mice with short telomeres (G3Terc−/−) had an improved short-term memory deficit through reducing dentate gyrus neurogenesis and loss of neurons in the hippocampus and frontal cortex, as compared to mice with long telomere reserves (Terc+/+) (Rolyan et al. 2011).

Collectively, there is still controversy about the role of telomere shortening in cognitive function in AD (Fig. 1). Thus, further research about the role of telomere shortening in cognitive function in AD is necessary and may help to clarify the very exact mechanisms.

Conclusion and Perspectives

Telomeres, like all DNA, are made up of units called nucleotides, arranged like beads on a string in the repeating sequence. A significant correlation is found between biological aging and telomere length. Many aging-related diseases are associated with shortened telomere length, including cancer, cardiovascular disease, AD, osteoporosis, osteoarthritis, diabetes and the physical signs of aging. Telomere shortening has contributed to the process of neurodegeneration and neurodegenerative diseases. Telomere shortening is linked with the pathogenesis of AD via oxidative stress and inflammation. Telomere shortening plays an important role in cognitive function in AD. Therefore, it seems that telomere length therapy, as a very attractive drug target, is an effective measure for AD. There are many questions about whether telomere shortening is a cause or consequence of AD, What is the mechanism between telomere shortening and AD pathology? What is the mechanism of cognitive impairment resulting in telomere shortening? What is the role of apoptosis in telomere shortening to AD?

Telomerase, a preexisting telomere repair system when activated, has been increasingly studied in the treatment for aging-related diseases. Scientific literature has well confirmed the role of telomerase in the immortal growth of reproductive cells. TA-65, as a telomerase activator, seems to add length to these critically short segments and target them to grow longer instead of shorter, and thus reverses aging or at least slows it down (de Jesus et al. 2011; Harley et al. 2011). The compound, TA-65, has been available to the general public for over 2 years now. The results are shown the improvements in the immune system function and bone density as well as better insulin levels (Harley et al. 2011). Furthermore, there is little doubt about the potential for increased risk of cancer due to TA-65. However, the TA-65 users report much stronger sex drive and energy after taking TA-65, which are difficult to quantify.

With the announcement that the Nobel Prize in Physiology or Medicine 2009 was awarded “for telomere biology” (Perona 2010; van der Harst et al. 2009), anti-aging medicine will be more and more concerned with the research of telomere biology. What is the role of telomere length therapy in AD? It is necessary to further clarify telomere-related pathogenesis in AD and explore clinical telomere-related agents.

Acknowledgments

This work was supported by the National Nature Science Foundation of China Grant (81070878/H0902) to Prof. Bin Zhao.

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© Springer Science+Business Media New York 2012