DYSREGULATED MTOR SIGNALING IS A SEMINAL STEP IN ALZHEIMER'S DISEASE PATHOGENESIS

Abstract

Brain insulin resistance, an Alzheimer’s disease (AD) hallmark that is provoked by amyloid-β oligomers (AβOs) (Bomfim, et al. 2012. J Clin Inv 122: 1339-1353), is a potentially fundamental driver of AD symptoms, but the mechanisms by which it causes the synaptic dysfunction and neuron death that underlie memory and cognitive impairment had remained unknown. Neuron death in AD is often caused by ectopic cell cycle re-entry (CCR) mediated by AβOs and tau, the precursors of plaques and tangles in AD brain. Primary mouse neurons treated with AβOs, 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. CCR of cultured neurons, which occurs within hours of initial AβO exposure, was prevented by inhibition or reduction of the multi-subunit protein kinase complexes, mTORC1 or mTORC2, or the small GTPase Rac1, which targets both complexes to membranes. CCR also requires mTORC1-dependent tau phosphorylation at S262. AβOs activate mTORC1 at the plasma membrane (PM), but not at lysosomes, where mTORC1 is activated instead by either insulin or amino acids, which block CCR. Reducing Rac1-dependent targeting of mTOR to the PM, forcing mTORC1 onto lysosomes or downregulating the lysosomal mTORC1 inhibitors, TSC complex or GATOR 1, also prevents CCR. Genetic reduction of mTOR in AD model mice strongly suppressed CCR and tau phosphorylation at S262, the latter of which was also reduced by the mTOR inhibitor, rapamycin. Finally, analysis of rapidly fixed human brain biopsy samples revealed that plaques and tangles strongly correlate with neuronal CCR, and tau phosphorylation at S262, S409 and S416, the latter of which we previously showed must be phosphorylated for CCR to proceed in response to AβO exposure (Seward, et al. 2013. J Cell Sci 126: 1278-1286). AβOs dysregulate normal mTOR signaling by activating mTORC1 at the cell surface while preventing insulin from stimulating lysosomal mTORC1. The ability of AβOs to provoke brain insulin resistance unleashes their toxic potential to cause neuronal CCR.