Abstract
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.
Current Alzheimer Research
Title:Mechanisms Involved in BACE Upregulation Associated to Stress
Volume: 9 Issue: 7
Author(s): Eva Martisova, Maite Solas, Gorka Gerenu, Fermin I. Milagro, Javier Campion and Maria J. Ramirez
Affiliation:
Keywords: Maternal separation, JNK, Alzheimer´s disease, epigenietic changes, mineralocorticoid receptors, corticosterone, Aβ, neuroblastoma cells, tau phosphorylation.
Abstract: 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.
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Cite this article as:
Martisova Eva, Solas Maite, Gerenu Gorka, I. Milagro Fermin, Campion Javier and J. Ramirez Maria, Mechanisms Involved in BACE Upregulation Associated to Stress, Current Alzheimer Research 2012; 9 (7) . https://dx.doi.org/10.2174/156720512802455368
DOI https://dx.doi.org/10.2174/156720512802455368 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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