Impact of Aging: Sporadic, and Genetic Risk Factors on Vulnerability to Apoptosis in Alzheimer's Disease

Abstract

The identification of specific genetic and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4 + T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4 + T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4 + and CD8 + T cells.

Enhanced apoptosis, oxidative stress and mitochondrial dysfunction in lymphocytes as potential biomarkers for Alzheimer’s disease

“…2) (Parshad et al, 1996;Eckert et al, 2001b;Schindowski et al, 2003), supporting the idea that AD specific changes lead to elevated susceptibility of T lymphocytes.…”

“…No changes in subset distribution of T, B or NK cells were found in AD patients compared to aged controls (Schindowski et al, 2003(Schindowski et al, , 2006. In contrast, a significant decrease in T lymphocytes was determined in healthy persons >60 years compared to young persons <30 years (Schindowski et al, 2002).…”

“…In contrast, a significant decrease in T lymphocytes was determined in healthy persons >60 years compared to young persons <30 years (Schindowski et al, 2002). Again, no changes in the distribution of T lymphocyte population in AD patients compared to aged controls were found (Schindowski et al, 2003(Schindowski et al, , 2006Frey et al, 2006), but a significant loss of CD3 þ , CD4 þ and CD8 þ occurred during aging. Interestingly, several recent findings indicate that mainly CD4 þ cells contribute to the increased apoptotic levels in peripheral lymphocytes of AD patients, whereas no changes in the susceptibility of CD8 þ T cells to apoptosis were determined ( Fig.…”

“…Interestingly, several recent findings indicate that mainly CD4 þ cells contribute to the increased apoptotic levels in peripheral lymphocytes of AD patients, whereas no changes in the susceptibility of CD8 þ T cells to apoptosis were determined ( Fig. 2) (Schindowski et al, 2003(Schindowski et al, , 2006Frey et al, 2006). Besides aging, apolipoprotein E (ApoE) genotype is the most important risk factor for sporadic AD.…”

Activated mTOR and PKR Kinases in Lymphocytes Correlate with Memory and Cognitive Decline in Alzheimer’s Disease

“…In AD biological abnormalities involving cells and tissues outside the central nervous system have already been reported in the literature [24] . For example in a previous study the levels of ␣ 1 -antichymotrypsin in plasma and cerebrospinal fluid of AD patients correlated with the results of cognitive tests [25] .…”