Loss of neuronal cell cycle control as a mechanism of neurodegeneration in the Presenilin-1 Alzheimer's disease brain

Bilal Malik, Antonio Currais, Ana Andres, Christopher Towlson, Didier Pitsi, Ana Nunes, Michael Niblock, Jonathan Cooper, Tibor Hortobágyi and Salvador Soriano

volume 7 | issue 5

1 March 2008
Pages: 637 - 646

This is an open-access article

Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.

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 treatment with the cell cycle inhibitor quercetin, but not by γ-secretase inhibition. Furthermore, β-catenin accumulates in neurons and adult hippocampus of PS1 KIM146V mice, as well as in temporal cortex of PS1 FAD patients, strongly suggesting an initiating role for aberrant β-catenin signalling in cell cycle-driven neuronal apoptosis. The present work identifies a novel mechanism by which PS1 mutations may exacerbate neurodegeneration in the FAD brain beyond dysregulation of γ-secretase activity, and it lends support to the notion that Alzheimer’s disease may be, at least in part, a disease driven by loss of cell cycle control.