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Alzheimers Dement. 2017 Feb;13(2):152-167. doi: 10.1016/j.jalz.2016.08.015. Epub 2016 Sep 29.

mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease.

Author information

1
Department of Biology, University of Virginia, Charlottesville, VA, USA. Electronic address: an2r@virginia.edu.
2
Department of Biology, University of Virginia, Charlottesville, VA, USA.
3
Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
4
Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, Tempe, AZ, USA.
5
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
6
Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. Electronic address: gsb4g@virginia.edu.

Abstract

A major obstacle to presymptomatic diagnosis and disease-modifying therapy for Alzheimer's disease (AD) is inadequate understanding of molecular mechanisms of AD pathogenesis. For example, impaired brain insulin signaling is an AD hallmark, but whether and how it might contribute to the synaptic dysfunction and neuron death that underlie memory and cognitive impairment has been mysterious. Neuron death in AD is often caused by cell cycle reentry (CCR) mediated by amyloid-β oligomers (AβOs) and tau, the precursors of plaques and tangles. We now report that CCR results from AβO-induced activation of the protein kinase complex, mTORC1, at the plasma membrane and mTORC1-dependent tau phosphorylation, and that CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. AβOs were also shown previously to reduce neuronal insulin signaling. Our data therefore indicate that the decreased insulin signaling provoked by AβOs unleashes their toxic potential to cause neuronal CCR, and by extension, neuron death.

KEYWORDS:

Alzheimer's disease; Amyloid-β oligomers; Cell cycle reentry; Diabetes; Insulin; Rac1; Tau

PMID:
27693185
PMCID:
PMC5318248
DOI:
10.1016/j.jalz.2016.08.015
[Indexed for MEDLINE]
Free PMC Article

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