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P3‐036: Rage signal transduction and implications for neuroinflammation in Alzheimer's disease
Author(s) -
Derk Julia,
Rosario Rosa,
Mathews Paul,
Schmidt Ann Marie
Publication year - 2015
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.2015.06.902
Subject(s) - rage (emotion) , neuroinflammation , signal transduction , microglia , medicine , endocrinology , receptor , microbiology and biotechnology , inflammation , neuroscience , biology
Background: mTOR, the protein kinase subunit of the mTORC1 and mTORC2 multiprotein complexes, plays a major role in cell proliferation and is hyperactivated in Alzheimer’s disease (AD). Amyloid-b (Ab) and tau respectively accumulate as insoluble plaques and tangles in AD brain, where ectopic cell cycle re-entry (CCR) leads to massive neuron death, which along with synaptic dysfunction, causes memory and cognitive loss. Neuronal CCR results partly from soluble Ab oligomers (AbOs) activating fyn, PKA and CaMKII, which respectively phosphorylate soluble tau at Y18, S409 and S416 (Seward, et al. 2013. J Cell Sci126: 1278-1286). We now report that Rac1-mediated mTOR dysregulation underlies AbO-induced CCR. Methods: Primary mouse neurons treated with AbOs, and Tg2576 and 3xTg mouse brains were used to model AD. Neurons were analyzed by immunoblotting and immunofluorescence, the latter of which was used to examine the mouse brains and human brain biopsies from elderly, normal pressure hydrocephalus patients. Results: In cultured neurons, inhibition or reduction of mTORC1, mTORC2 or Rac1 blocks AbO-induced CCR, which requires mTORC1-dependent phosphorylation of tau at S262. AbOs activate mTORC1 at the plasma membrane (PM), but not at lysosomes, where mTORC1 activation by insulin blocks CCR. Reducing Rac1-dependent targeting of mTOR to PM, forcing mTORC1 onto lysosomes, or knocking down the lysosomal mTORC1 inhibitors, Nprl3 or Tsc2, also prevents CCR. In Tg2576 mice, genetic reduction of mTOR blocks CCR and tau phosphorylation at S262, the latter of which is reduced by rapamycin in 3xTg mice. In human brain, plaques and tangles strongly correlate with CCR, and tau phosphorylation at S262, S409 and S416. Conclusions:Compared to insulin, which activates mTORC1 at the PM and lysosomes, mTORC1 activation by AbOs solely at the PM represents a fundamental dysregulation of mTOR signaling that translates into tau-dependent neuronal CCR in AD. AbOs also trigger insulin resistance in neurons (Bomfim, et al. 2012. J Clin Invest 122, 1339-1353), however, and are thus a two-edged sword that both provoke insulin insensitivity and explain a fatal downstream consequence: CCR and eventual neuron death. These dual effects of AbOs provide a mechanistic justification for AD’s classification as type 3 diabetes. P3-036 RAGE SIGNALTRANSDUCTION AND IMPLICATIONS FOR NEUROINFLAMMATION IN ALZHEIMER’S DISEASE