Glucocorticoid enhances presenilin1-dependent A beta production at ER's mitochondrial-associated membrane by downregulating Rer1 in neuronal cells

Stress-induced release of glucocorticoid is an important amyloidogenic factor that upregulates amyloid precursor protein (APP) and beta secretase 1 (BACE1) levels. Glucocorticoid also contributes to the pathogenesis of Alzheimer's disease (AD) by increasing ER-mitochondria connectivity, in which amyloid beta (A beta) processing occurs rigorously because of its lipid raft-rich characteristics. However, the mechanism by which glucocorticoid enhances gamma-secretase activity in the mitochondrial-associated membrane of ER (MAM) and subsequent accumulation of mitochondrial A beta is unclear. In this study, we determined how glucocorticoid enhances A beta production in MAM using SH-SY5Y cells and ICR mice. First, we observed that cortisol-induced A beta accumulation in mitochondria preceded its extracellular apposition by enhancing gamma-secretase activity, which was the result of increased presenilin 1 (PSEN1) localization in MAM. Screening data revealed that cortisol selectively down-regulated the ER retrieval protein Rer1, which triggered its maturation and subsequent entry into the endocytic secretory pathway of PSEN1. Accordingly, overexpression of RER1 reversed the deleterious effects of mitochondrial A beta on mitochondrial respiratory function and neuronal cell viability. Notably, we found that cortisol guided the glucocorticoid receptor (GR) to bind directly to the RER1 promoter, thus trans-repressing its expression. Inhibiting GR function reduced A beta accumulation at mitochondria and improved the outcome of a spatial memory task in mice exposed to corticosterone. Taken together, glucocorticoid enhances PSEN1-mediated A beta generation at MAM by downregulating Rer1, which is a potential target at early stages of AD pathogenesis.