Apolipoprotein E epsilon 4 is associated with an increased vulnerability to cell death in Alzheimer’s disease

Abstract

The presumption to suffer from Alzheimer's disease (AD) accelerates with aging. One important risk factor seems to be the isoform epsilon 4 of the apolipoprotein E gene (Apo epsilon 4), which increases the risk to develop AD at an earlier age. Furthermore, convincing evidence is provided that apoptotic cell death mechanisms play an important role in neuronal cell death in AD. In the present study, we investigated whether abnormalities in apoptosis and caspase-3 activity can be found at the level of lymphocytes and a T cell subtype, CD4 T cells, from AD patients compared to aged sex- and ApoE genotype-matched non-demented controls. Under different experimental conditions (at baseline or after in vitro incubation in the presence of proapoptotic stimuli) increased levels of apoptosis and enhanced caspase-3 activity were detected in lymphocytes from AD patients. This difference was most pronounced in the CD4(+) T cell subtype. Notably, we found a significant increase of apoptotic cells and caspase-3 activity in lymphocytes from AD patients bearing one or two alleles of the ApoE4 compared to non-E4 carriers. Again, these effects were strongest in CD4(+) T cells. Circulating amyloid-beta (A beta) levels did not differ between AD patients bearing ApoE4 and non-ApoE4 and age-matched controls. Therefore, it is likely that circulating A beta is not responsible for the observed effects, which might rather reflect an ongoing systemic response in AD, e.g. an increase in CD95 expression.

APOE epsilon‐4 allele and cytokine production in Alzheimer's disease

“…Nevertheless, prior to ours, animal studies have displayed APOE-dependent variations in morphology and function in microglia cells and peripheral macrophages (Vitek et al, 2007;Brown et al, 2008). In addition a significant increase in cell apoptosis was reported in lymphocytes from AD patients bearing one or two alleles of the APOE4 compared to non-E4 carriers (Frey et al, 2006). TNF-a and IL-1b released by mononuclear cells did not correlate with the clinical features of AD in our patients.…”

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

“…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.…”

“…Importantly, a robust difference in cell death sensitivity between AD patients and patients suffering from vascular dementia was detected. Moreover, increased CD 95 expression on the surface of T cells from sporadic AD patients and elevated caspase-3, caspase-8 and caspase-9 levels in comparison with nondemented controls refer to an enhanced proneness of AD lymphocytes to cell death (Lombardi et al, 2004;Tacconi et al, 2004;Frey et al, 2006). These findings suggest involvement of the extrinsic and intrinsic apoptotic pathway.…”

“…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.…”

Increased T-cell Reactivity and Elevated Levels of CD8+ Memory T-cells in Alzheimer’s Disease-patients and T-cell Hyporeactivity in an Alzheimer’s Disease-mouse Model: Implications for Immunotherapy

“…There are numerous reports concerning changes in T-cells from AD patients concerning distribution (Singh 1990;Pirttila et al 1992;Shalit et al 1995;Lombardi et al 1999;Tan et al 2002;Schindowski et al 2006) and function including altered basal expression of activation markers (Ikeda et al 1991a, b;Shalit et al 1995;Bongioanni et al 1997b;Lombardi et al 1999), disturbed Calcium homeostasis (Adunsky et al 1991;Grossmann et al 1993;Adunsky et al 1995;Eckert et al 1995;Ibarreta et al 1997;Palotas et al 2002), altered cytokine secretion (Shalit et al 1995;Bongioanni et al 1997aBongioanni et al , b, 1998Monsonego et al 2003;Sala et al 2003;Iarlori et al 2005;Galimberti et al 2006;Rota et al 2006), impaired proliferation (Shalit et al 1995;Lombardi et al 1999;Stieler et al 2001), and increased apoptosis (Lombardi et al 1999;Maesaka et al 1999;Eckert et al 2001a;Panossian et al 2003;Schindowski et al 2003;Dorszewska et al 2005;Frey et al 2006;Schindowski et al 2006). Remarkably, Ab stimulates lymphocytes from healthy donors, however, lymphocytes from AD patients do not respond upon Ab exposure (Eckert et al 1995;Trieb et al 1996) reflecting hyporeactivit...…”