Mechanisms involved in BACE upregulation associated to stress.
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.
Department of Pharmacology, School of Medicine, University of Navarra, C/ Irunlarrea, 1, 31008 Pamplona, Spain.
Eva
E
Martisova
Maite
M
Solas
Gorka
G
Gerenu
Fermin I
FI
Milagro
Javier
J
Campion
Maria J
MJ
Ramirez
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003345:Corticosterone / Q000494:pharmacology; D019175:DNA Methylation; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D008426:Maternal Deprivation; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000494:pharmacology; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000451:Mineralocorticoid Receptor Antagonists; D010455:Peptides; D013148:Spironolactone; D048670:MAP Kinase Kinase 4; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; C478085:D-JNKI-1; D003345:Corticosterone