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bioRxiv · 10.1101/322610

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

Choi, G. E.·Oh, J. Y.·Lee, H. J.·Chae, C. W.·Kim, J. S.·Jung, Y. H.·Han, H. J.
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Abstract

We investigated glucocorticoid, a major risk factor of Alzheimers 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, A{beta} was produced since {gamma}-secretase activity was upregulated by increased ER-mitochondria connectivity. Mitochondrial Ca2+ influx was also elevated due to ER-mitochondria bridging, resulting in activation of mTOR pathway. Subsequent autophagy inhibition failed to remove A{beta} and led to its accumulation. Moreover, selective autophagy through ubiquitination of SCG10 was suppressed. We eventually showed that both elevated A{beta} 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 A{beta} generation and SCG10 upregulation. Subsequent microtubule destabilization leads to memory impairment through failure of AMPAR1/2 or mitochondria transport into cell periphery.

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Choi, G. E., Oh, J. Y., Lee, H. J., Chae, C. W., Kim, J. S., Jung, Y. H., Han, H. J.. 2018-05-14. Glucocorticoid-mediated Aβ and SCG10 upregulation evoke microtubule dysfunction and memory deficits. https://doi.org/10.1101/322610

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