Panossian, L.A. et al. Telomere shortening in T cells correlates with Alzheimer's disease status. Neurobiol. Aging 24, 77-84

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Ángeles, California, United States
Neurobiology of Aging (Impact Factor: 5.01). 01/2003; 24(1):77-84. DOI: 10.1016/S0197-4580(02)00043-X
Source: PubMed


Telomeres, the repeated sequences that cap chromosome ends, undergo shortening with each cell division, and therefore serve as markers of a cell's replicative history. In vivo, clonal expansion of T cells during immune responses to both foreign and autoantigens is associated with telomere shortening. To investigate possible immune alterations in Alzheimer's disease (AD) that might impact current vaccine-based therapeutic strategies, we analyzed telomere lengths in immune cell populations from AD patients. Our data show a significant telomere shortening in PBMC from AD versus controls (P=0.04). Importantly, telomere length of T cells, but not of B cells or monocytes, correlated with AD disease status, measured by Mini Mental Status Exam (MMSE) scores (P=0.025). T cell telomere length also inversely correlated with serum levels of the proinflammatory cytokine TNFalpha (a clinical marker of disease status), with the proportion of CD8+ T cells lacking expression of the CD28 costimulatory molecule, and with apoptosis. These findings suggest an immune involvement in AD pathogenesis.

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    • "To date, investigations on blood cells have been inconsistent in relationship between TL and AD [38] [39] [40] [41] [42] [43] [44] [45] [46] [47]. In particular, several studies reported that TL is associated with cognitive decline in elders [48] [49] [50] [51] and is shorter in patients with AD [38] [39] [40] [41] [42] [43] [44], but other studies showed TL is not associated with either levels of cognitive performance or age-related cognitive change [52] [53] and cannot be used in elderly as marker to diagnose the early phase of cognitive impairment (mild cognitive impairment), to distinguish between demented and non-demented patients and/or the type of dementia [45] [46] [47]. A growing body of literature shows that inflammation is involved in the neurodegeneration process [54] [55] [56] [57] [58] and can furthermore accelerate telomere shortening [26] [27] [28] [29], which, in turn, may be linked with the pathogenesis of AD [38–44, 59–61]. "
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    ABSTRACT: Background: Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes. Objective: The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-β (Aβ)-stimulated PBMC. Methods: We enrolled 31 late-onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up ≤3 points) or fast progressing AD (ADF) (MMSE decline ≥5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay. Results: TL (mean±SD) for HE, ADS, and ADFwas 2.3±0.1, 2.0±0.1, and 2.5±0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p = 0.034) and to ADF (p = 0.005). MMSE decline correlated with TL in AD (R2 = 0.284; p = 0.008). We found a significant difference in IL-10 production between unstimulated and Aβ-stimulated PBMC from ADS (40.7±13.7 versus 59.0±27.0; p = 0.004) but not from ADF (39.7±14.4 versus 42.2±22.4). HE showed a trend toward significance (47.1±25.4 versus 55.3±27.9; p = 0.10). Conclusion: PBMC from ADF may be characterized by an impaired response induced by Aβ and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression.
    Journal of Alzheimer's disease: JAD 06/2015; 46(3):761-769. DOI:10.3233/JAD-142808 · 4.15 Impact Factor
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    • "Mutations that decrease telomerase and cause short telomeres in humans lead to a spectrum of premature-onset diseases and conditions collectively termed " telomere syndromes, " which share many features of the common diseases of aging in the human population (Armanios and Blackburn 2012). Multiple independent studies have found impaired human telomeric DNA length maintenance to be associated with a wide range of diseases and for several age-related diseases to predict future risks and outcomes including mortality (Von Zglinicki et al. 2000; Samani et al. 2001; Cawthon et al. 2003; Panossian et al. 2003; Valdes et al. 2005; Bischoff et al. 2006; Harris et al. 2006; Martin- Ruiz et al. 2006; Bakaysa et al. 2007; Brouilette et al. 2007; Fitzpatrick et al. 2007, 2011; Aubert and Lansdorp 2008; Farzaneh-Far et al. 2008; Kimura et al. 2008; Epel et al. 2009; Njajou et al. 2009; Astrup et al. 2010; Codd et al. 2010, 2013; Salpea et al. 2010; Willeit et al. 2010a,b; Zee et al. 2010; Strandberg et al. 2011; Wentzensen et al. 2011; Yaffe et al. 2011; Honig et al. 2012; Lee et al. 2012; Weischer et al. 2012; Bojesen 2013; Muezzinler et al. 2013; Gardner et al. 2014; Haycock et al. 2014; Walsh et al. 2014). "
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    ABSTRACT: The Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis. Copyright © 2015, The Genetics Society of America.
    Genetics 06/2015; 200(4). DOI:10.1534/genetics.115.178624 · 5.96 Impact Factor
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    • "Environmental and Molecular Mutagenesis . DOI 10 . 1002 / em bridge cycles [ Kruk et al . , 1995 ; Surralles et al . , 1999 ; O ' Sullivan et al . , 2002 ; Panossian et al . , 2003 ; Fenech , 2006 , 2007 ]"
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    ABSTRACT: DNA damage may play a key role in promoting disease-onset and accelerated disease progression in Alzheimer's disease (AD) by increasing the rates of neuronal cell death. The ɛ4 allele of the APOE gene is the best characterised genetic risk factor for AD, however, it is unknown if APOE ɛ4 carriers exhibit increased levels of DNA damage which may contribute to increased AD risk. 175 healthy participants (aged 34-67 years old) from South Australia were recruited into the study and provided a single blood sample for the isolation of peripheral blood lymphocytes, APOE genotyping and lymphocyte chromosomal DNA damage analysis using the Cytokinesis-Block micronucleus cytome (CBMN-Cyt) assay with the micronucleus index being the primary outcome measure. When compared to non-APOE ɛ4 carriers, APOE ɛ4 carriers did not exhibit altered rates of i) cell division, represented by the nuclear division index (NDI, P = 0.372), ii) cell death as represented by apoptotic (P = 0.457) and necrotic (P = 0.393) frequencies and iii) chromosomal DNA damage as indicated by the number of micronuclei (MNi, P = 0.795), nucleoplasmic bridges (NPBs, P = 0.221) or nuclear buds (NBUDs, P = 0.293) scored in binucleated cells. In conclusion, although we and others have previously shown that rates of chromosomal DNA damage measured using the CBMN-Cyt assay are elevated in individuals with cognitive impairment, in this South Australian cohort the frequency of genome instability is not substantially influenced by the presence of the APOE ɛ4 allele. Environ. Mol. Mutagen., 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 03/2015; 56(8). DOI:10.1002/em.21949 · 2.63 Impact Factor
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