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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cell Cycle / physiology*
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cerebral Cortex / metabolism
  • Humans
  • Hydrocephalus, Normal Pressure / metabolism
  • Insulin / metabolism
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Mice, Knockout
  • Middle Aged
  • Neurons / metabolism*
  • tau Proteins / genetics
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Insulin
  • MAPT protein, human
  • Mapt protein, mouse
  • tau Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2