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

Andrés Norambuena, Horst Wallrabe, Lloyd McMahon, Antonia Silva, Eric Swanson, Shahzad S. Khan, Daniel Baerthlein, Erin Kodis, Salvatore - Oddo, James W. Mandell, George S. Bloom

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)152-167
Number of pages16
JournalAlzheimer's and Dementia
Volume13
Issue number2
DOIs
Publication statusPublished - Feb 1 2017

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Keywords

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

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Geriatrics and Gerontology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

Norambuena, A., Wallrabe, H., McMahon, L., Silva, A., Swanson, E., Khan, S. S., ... Bloom, G. S. (2017). mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease. Alzheimer's and Dementia, 13(2), 152-167. https://doi.org/10.1016/j.jalz.2016.08.015