科研之友
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摘要
Glucocorticoid has been widely accepted to induce Alzheimer's disease, but the nongenomic effect of glucocorticoid on amyloid beta (A beta) generation has yet to be studied. Here, we investigated the effect of the nongenomic pathway induced by glucocorticoid on amyloid precursor protein processing enzymes as well as A beta production using male ICR mice and human neuroblastoma SK-N-MC cells. Mice groups exposed to restraint stress or intracerebroventricular injection of A beta showed impaired cognition, decreased intracellular glucocorticoid receptor (GR) level, but elevated level of membrane GR (mGR). In this respect, we identified the mGR-dependent pathway evoked by glucocorticoid using impermeable cortisol conjugated to BSA (cortisol-BSA) on SK-N-MC cells. Cortisol-BSA augmented the expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), the level of C-terminal fragment beta of amyloid precursor protein (C99) and A beta production, which were maintained even after blocking intracellular GR. Wealso found that cortisol-BSA enhanced the interaction between mGR and G alpha s, which colocalized in the lipid raft. The subsequently activated CREB by cortisol-BSA bound to the CRE site of the BACE1 promoter increasing its expression, which was downregulated by inhibiting CBP. Consistently, blocking CBP attenuated cognitive impairment and A beta production induced by corticosterone treatment or intracerebroventricular injection of A beta more efficiently than inhibiting intracellular GR in mice. In conclusion, glucocorticoid couples mGR with G alpha s and triggers cAMP-PKA-CREB axis dependent on the lipid raft to stimulate BACE1 upregulation and A beta generation.
- 出版日期2017-8-30
