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Cell cycle‐driven neuronal apoptosis specifically linked to amyloid peptide Aβ 1–42 exposure is not exacerbated in a mouse model of presenilin‐1 familial Alzheimer’s disease
Author(s) -
Malik Bilal,
Currais Antonio,
Soriano Salvador
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05446.x
Subject(s) - presenilin , cell cycle , neurodegeneration , biology , apoptosis , programmed cell death , microbiology and biotechnology , cell cycle checkpoint , alzheimer's disease , genetics , medicine , disease
We have shown previously that β‐catenin and cyclin D1 are up‐regulated in cortical neurons from homozygous mice carrying the familial Alzheimer’s disease (FAD) presenilin‐1 M146V mutation in a knock‐in model (PS1 KI M146V mice), leading to cell cycle‐associated apoptosis. Here, we have aimed to determine (i) whether this phenotype is present in heterozygous PS1 KI M146V mice, which reflects more accurately the PS1 FAD condition in humans and (ii) whether Aβ 1–42 , which is invariably present in the PS1 FAD brain and is thought to affect neuronal cell cycle kinetics, may contribute to the abnormal cell cycle/cell death phenotype seen in PS1 KI M146V mice. We demonstrate that cell cycle‐linked apoptosis occurs in heterozygous PS1 KI M146V post‐mitotic neurons. In addition, there is a significant Aβ‐associated increase in cell cycle and cell death that is not further modified by the PS1 KI M146V mutation. Our results are consistent with a cell cycle‐associated neurodegeneration model in the PS1 FAD brain in which the loss of PS1‐dependent β‐catenin regulatory function is sufficient to commit susceptible neurons to an abortive cell cycle, and may act synergistically with the Aβ cytotoxic challenge present in the PS1 FAD brain to expand the neuronal population susceptible to cell cycle‐driven apoptosis.