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mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease
Author(s) -
Norambuena Andrés,
Wallrabe Horst,
McMahon Lloyd,
Silva Antonia,
Swanson Eric,
Khan Shahzad S.,
Baerthlein Daniel,
Kodis Erin,
Oddo Salvatore,
Mandell James W.,
Bloom George S.
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.08.015
Subject(s) - mtorc1 , neuroscience , pi3k/akt/mtor pathway , neuron , insulin receptor , insulin , programmed cell death , cyclin dependent kinase 5 , signal transduction , biology , medicine , kinase , microbiology and biotechnology , protein kinase a , apoptosis , insulin resistance , biochemistry , mitogen activated protein kinase kinase
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.