Glucocorticoid-mediated Aβ and SCG10 upregulation evoke microtubule dysfunction and memory deficits

We investigated glucocorticoid, a major risk factor of Alzheimer’s disease, promoted microtubule instability that culminates in memory deficits. Mice group exposed to corticosteroid had reduced trafficking of AMPAR1/2 and mitochondria into the synapse due to microtubule destabilization, which finally impaired cognitive function. Furthermore, cortisol reduced microtubule stability through the mitochondria glucocorticoid receptor (GR)-dependent pathway in SH-SY5Y cells. Cortisol translocated the Hsp70-bound GR into mitochondria before stimulating ER-mitochondria interaction via increasing GR-Bcl-2 complex. Subsequently, Aβ was produced since γ-secretase activity was upregulated by increased ER-mitochondria connectivity. Mitochondrial Ca 2+ influx was also elevated due to ER-mitochondria bridging, resulting in activation of mTOR pathway. Subsequent autophagy inhibition failed to remove Aβ and led to its accumulation. Moreover, selective autophagy through ubiquitination of SCG10 was suppressed. We eventually showed that both elevated Aβ and SCG10 levels drive cells to fail trafficking AMPAR1/2 and mitochondria into the cell terminus. In conclusion, glucocorticoid regulates ER-mitochondria coupling, which evokes Aβ generation and SCG10 upregulation. Subsequent microtubule destabilization leads to memory impairment through failure of AMPAR1/2 or mitochondria transport into cell periphery.