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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    • "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; DOI:10.1002/em.21949 · 2.63 Impact Factor
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    • "In addition, it has been often reported that the rate of telomere shortening is variable within the elderly population and that this is associated with metabolic decline, increased risk for age-related diseases and death (Finch 2007; Njajou et al. 2007). TL is then considered a biomarker of age-related physical decline and of survival expectation (Kim Sh et al. 2002; Panossian et al. 2003; Benetos et al. 2004; Brouilette et al. 2007). Telomerases are part of a specialized ribonucleoprotein complex that adds the telomere repeats to the ends of chromosomes. "
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    ABSTRACT: Leukocyte telomere length (LTL) has been observed to be hereditable and correlated with longevity. However, contrasting results have been reported in different populations on the value of LTL heritability and on how biology of telomeres influences longevity. We investigated whether the variability of genes correlated to telomere maintenance is associated with telomere length and affects longevity in a population from Southern Italy (20-106 years). For this purpose we analyzed thirty-one polymorphisms in eight telomerase-associated genes of which twelve in the genes coding for the core enzyme (TERT and TERC) and the remaining in genes coding for components of the telomerase complex (TERF1, TERF2, TERF2IP, TNKS, TNKS2 and TEP1). We did not observe (after correcting for multiple testing) statistically significant associations between SNPs and LTL, possibly suggesting a low genetic influence of the variability of these genes on LTL in the elderly. On the other hand, we found that the variability of genes encoding for TERF1 and TNKS2, not directly involved in LTL, but important for keeping the integrity of the structure, shows a significant association with longevity. This suggests that the maintenance of these chromosomal structures may be critically important for preventing, or delaying, senescence and aging. Such a correlation was not observed in a population from northern Italy that we used as an independent replication set. This discrepancy is in line with previous reports regarding both the population specificity of results on telomere biology and the differences of aging in northern and southern Italy.
    Biogerontology 01/2015; 16(3). DOI:10.1007/s10522-015-9551-6 · 3.29 Impact Factor
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