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 β-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.We show that cyclin D1 is indeed upregulated in cortical neurons of mice expressing the knock-in PS1 FAD mutation M146V, as well as in temporal cortex of FAD patients expressing different PS1 mutations. Cyclin D1 upregulation in mutant neurons leads to cell cycle-driven apoptosis, a phenotype reversed by blocking entry into the cell cycle by small interfering RNA (siRNA) cyclin D1 downregulation and by tre...