The objective of the present work was to study a purported involvement of stress in amyloid pathology through
the modulation of BACE expression. Early-life stressed rats (maternal separation, MS) showed significant increases in
corticosterone levels, BACE expression and Aβ levels. The CpG7 site of the BACE promoter was significantly hypomethylated
in MS, and corticosterone levels negatively correlated to the methylation status of CpG7. The activation of
the stress-activated protein kinase JNK was also increased in MS rats. In SHSY-5Y neuroblastoma cells, corticosterone
induced a rapid increase in BACE expression that was abolished by specific inhibiton of JNK activation or by spironolactone,
a mineralocorticoid receptor antagonist, but not by mifepristone, a glucocorticoid receptor antagonist. Corticosterone
was also able to increase pJNK expression and this effect was fully reverted by spironolactone. Mice chronically treated
with corticosterone showed increased BACE and pJNK expression. These increases were reverted by treatment with spironolactone
or with a JNK inhibitor. It is suggested that increased corticosterone levels associated to stress lead to increase
BACE transcription both through epigenetic mechanisms and activation of JNK.
Keywords: Maternal separation, JNK, Alzheimer´s disease, epigenietic changes, mineralocorticoid receptors, corticosterone,
Aβ, neuroblastoma cells, tau phosphorylation.
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