Cell cycle-driven neuronal apoptosis specifically linked to amyloid peptide Abeta1-42 exposure is not exacerbated in a mouse model of presenilin-1 familial Alzheimer's disease.
We have shown previously that beta-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 Abeta(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 Abeta-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 beta-catenin regulatory function is sufficient to commit susceptible neurons to an abortive cell cycle, and may act synergistically with the Abeta cytotoxic challenge present in the PS1 FAD brain to expand the neuronal population susceptible to cell cycle-driven apoptosis.
Malik
Bilal
B
Department of Neuroscience, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, De Crespigny Park, London, UK.
Currais
Antonio
A
Soriano
Salvador
S
D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D053764:Presenilin-1 / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D051176:beta Catenin; D019938:Cyclin D1; D001973:Bromodeoxyuridine