mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease.
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.
Department of Biology, University of Virginia, Charlottesville, VA, USA. Electronic address: an2r@virginia.edu.
Andrés
A
Norambuena
Department of Biology, University of Virginia, Charlottesville, VA, USA.
Horst
H
Wallrabe
Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
Lloyd
L
McMahon
Department of Biology, University of Virginia, Charlottesville, VA, USA.
Antonia
A
Silva
Department of Biology, University of Virginia, Charlottesville, VA, USA.
Eric
E
Swanson
Department of Biology, University of Virginia, Charlottesville, VA, USA.
Shahzad S
SS
Khan
Department of Biology, University of Virginia, Charlottesville, VA, USA.
Daniel
D
Baerthlein
Department of Biology, University of Virginia, Charlottesville, VA, USA.
Erin
E
Kodis
Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, Tempe, AZ, USA.
Salvatore
S
Oddo
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
James W
JW
Mandell
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.
George S
GS
Bloom
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D018345:Mice, Knockout; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D007328:Insulin; C054369:MAPT protein, human; C558298:Mapt protein, mouse; D016875:tau Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2
Alzheimer's disease; Amyloid-β oligomers; Cell cycle reentry; Diabetes; Insulin; Rac1; Tau
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