Loss of neuronal cell cycle control as a mechanism of neurodegeneration in the presenilin-1 Alzheimer's disease brain.
Presenilin-1 (PS1) is a component of the beta-catenin degradation machinery, and PS1 mutations linked to familial Alzheimer's disease (FAD) represent a loss of this function, leading, in non-neuronal cells, to accumulation of cyclin D1, aberrant cell cycle activation and hyperproliferation. In post-mitotic neurons, cell cycle activation is thought to be abortive and initiate apoptosis, thus contributing to AD pathogenesis. Consequently, we tested here the hypothesis that, in the PS1 FAD brain, cyclin D1 accumulation may occur and lead to neuronal apoptosis secondary to an abortive entry into the cell cycle.
Malik
Bilal
B
Department of Neuroscience, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, United Kingdom.
Currais
Antonio
A
Andres
Ana
A
Towlson
Christopher
C
Pitsi
Didier
D
Nunes
Ana
A
Niblock
Michael
M
Cooper
Jonathan
J
Hortobágyi
Tibor
T
Soriano
Salvador
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D053764:Presenilin-1 / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism
D004791:Enzyme Inhibitors; D050505:Mutant Proteins; D053764:Presenilin-1; D051176:beta Catenin; D019938:Cyclin D1; D011794:Quercetin; D053829:Amyloid Precursor Protein Secretases