Elevated Levels of Fragmented DNA Nucleosomes in Native and Activated Lymphocytes Indicate an Enhanced Sensitivity to Apoptosis in Sporadic Alzheimer’s Disease

Mechanisms of Ageing and Development

Fröhlich

Maurer

et al. 2002

Self Cite

The relevance of physiological immune aging is of great interest with respect to determining disorders with pathologic immune function in aging individuals. In recent years, the relevance of changes in peripheral lymphocytes in age-associated neurologic diseases has become more evident. Due to the lack of immunological studies. covering moce than one event after mitogenic activation, we envisaged a new concept in the present study, aiming to investigate several events, starting from T cell receptor (TCR) ligation up to T cell proliferation. In addition, we addressed the question whether changes are present in the subsets (CD4, CDR) with aging. Phosphorylation of tyrosine residues declines with increasing age in CD4+ cells. Fewer levels of CD69 positive cells after 4 h mitogenic activation, altered expression of cytokines (IL2, IFN-7 and TNF-a; 22 h) and lower proliferation (72 h) were detemined in aging. Moreover, it could be shown that CD8" lymphocytes react more effectively to mitogenic stirnulation with referenoe to CD69 expression and proliferation in both age groups ( < 35 and > 60 years old). These data indicate that T cell activation, rnediated by TCR engagement, is significantly impaired in aging and both subsets are affected. However, bypassing the TCR does not fully restore T cell function, indicating that there are more mechanisms involved than impaired signal transduction thwugh TCR only. The results will be discussed in relation to iiheir relevance in neurodegenerative and psychiatric disorders.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age-related impairment of human T lymphocytes’ activation: specific differences between CD4+ and CD8+ subsets

Mechanisms of Ageing and Development

Fröhlich

Maurer

et al. 2002

Self Cite

“…Low molecular weight DNA which is built during apoptosis is found only within the cell. As apoptosis proceeds in vitro, however, cells develop secondary in vitro necrosis which is characterized among other things by cell lysis and the appearance of DNA fragments in the supernatant (Watt et al, 1994;Eckert et al, 2000).…”

Section: Generation and Characterization Of Transgenic Micementioning

confidence: 99%

“…In addition, lymphocyte cell lines, e.g., the human Jurkat T-cell line, transfected with mutant PS1 (Passer et al, 1999) and lymphocytes from FAD patients bearing PS1 mutations (Parshad et al, 1996) show similar results in regard to increased vulnerability to DNA damage finally leading to accelerated cell death. Moreover, enhanced vulnerability to cell death and perturbed calcium homeostasis have also been described in peripheral lymphocytes from AD patients (Parshad et al, 1996;Eckert et al, 1997aEckert et al, , 1998Eckert et al, , 2000Gasparini et al, 1998).…”

Section: Introductionmentioning

confidence: 98%

Alzheimer's Disease-like Alterations in Peripheral Cells from Presenilin-1 Transgenic Mice

Eckert

Neurobiology of Disease

Leutner

et al. 2001

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Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Expression of PS1 mutations in cell culture systems and in primary neurons from transgenic mice increases their vulnerability to cell death. Interestingly, enhanced vulnerability to cell death has also been demonstrated for peripheral lymphocytes from AD patients. We now report that lymphocytes from PS1 mutant transgenic mice show a similar hypersensitivity to cell death as do peripheral cells from AD patients and several cell culture systems expressing PS1 mutations. The cell death-enhancing action of mutant PS1 was associated with increased production of reactive oxygen species and altered calcium regulation, but not with changes of mitochondrial cytochrome c. Our study further emphasizes the pathogenic role of mutant PS1 and may provide the fundamental basis for new efforts to close the gap between studies using neuronal cell lines transfected with mutant PS1, neurons from transgenic animals, and peripheral cells from AD patients.

“…In addition, lymphocyte cell lines (e.g., the human Jurkat T-cell line), transfected with mutant PS1 (Wolozin et al, 1998), and lymphocytes from FAD patients bearing PS1 mutations (Parshad et al, 1996) show similar results in regard to increased vulnerability to DNA damage leading to accelerated cell death. Moreover, enhanced vulnerability to cell death has also been described in peripheral lymphocytes from AD patients (Hartwig, 1995;Parshad et al, 1996;Eckert et al, 1998;Eckert et al, 2001a) but not in patients with vascular dementia (Hartwig, 1995;Eckert et al, 2001a). Oxidative stress mechanisms seem to influence this process (Gibson et al, 2000;Eckert et al, 2001a;Mecocci et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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

Kratzsch

Peters

et al. 2003

NMM

Self Cite

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.