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J Cell Sci. 2002 Aug 1;115(Pt 15):3131-8.

Selective impairment of p53-mediated cell death in fibroblasts from sporadic Alzheimer's disease patients.

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  • 1Department of Biomedical Sciences and Biotechnologies, University of Brescia, Brescia, Italy.

Abstract

In this study, we evaluated the response of different human skin fibroblast cultures obtained from eight probable Alzheimer's disease patients and eight non-Alzheimer's disease subjects to an acute oxidative injury elicited by H(2)O(2). This treatment generates reactive oxygen species, which are responsible for DNA damage and apoptosis. To compare the sensitivity of fibroblasts from Alzheimer's disease or non-Alzheimer's disease patients to H(2)O(2) exposure, we evaluated different parameters, including cell viability, the extension of DNA damage and the ability of the cells to arrest proliferation and to activate an apoptotic program. We found that fibroblasts from Alzheimer's disease patients were more resistant that those from control subjects to H(2)O(2) treatment, although the extent of DNA damage induced by the oxidative injury was similar in both experimental groups. The protective mechanism of Alzheimer's disease fibroblasts was related to an impairment of H(2)O(2)-induced cell cycle arrest and characterized by an accelerated re-entry into the cell cycle and a diminished induction of apoptosis. Fibroblasts from Alzheimer's disease patients also have a profound impairment in the H(2)O(2)-activated, p53-dependent pathway, which results in a lack of activation of p53 or p53-target genes, including p21, GADD45 and bax. This study demonstrates a specific alteration of an intracellular pathway involved in sensing and repairing DNA damage in peripheral cells from Alzheimer's disease patients.

PMID:
12118068
[PubMed - indexed for MEDLINE]
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