17β-Estradiol regulates insulin-degrading enzyme expression via an ERβ/PI3-K pathway in hippocampus: relevance to Alzheimer's prevention.

Title17β-Estradiol regulates insulin-degrading enzyme expression via an ERβ/PI3-K pathway in hippocampus: relevance to Alzheimer's prevention.
Publication TypeJournal Article
Year of Publication2011
AuthorsZhao L, Yao J, Mao Z, Chen S, Wang Y, Brinton RDiaz
JournalNeurobiol Aging
Volume32
Issue11
Pagination1949-63
Date Published2011 Nov
ISSN1558-1497
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Animals, Cells, Cultured, Estradiol, Estrogen Receptor beta, Female, Hippocampus, Insulysin, Mice, Mice, Transgenic, Neurons, Ovariectomy, Phosphatidylinositol 3-Kinases, Rats, Signal Transduction
Abstract

Insulin-degrading enzyme (IDE), an enzyme that primarily degrades insulin, has recently been demonstrated to play a significant role in the catabolism of amyloid β (Aβ) protein in the brain. Reduced IDE expression and/or activity have been associated with the etiology and development of Alzheimer's disease (AD). Using three model systems, the present investigation provides the first documentation indicating that estrogen robustly regulates the expression of IDE in normal, menopausal and early-stage AD brains. In vitro analyses in primary cultures of rat hippocampal neurons revealed that 17β-estradiol (17β-E2) increased IDE in both mRNA and protein levels in a time-dependent manner. Further pharmacological analyses indicated that 17β-E2-induced IDE expression was dependent upon estrogen receptor (ER) β and required activation of phosphatidylinositol 3-kinase (PI3-K). In vivo analyses in adult female rats revealed a brain region-specific responsive profile. Ovariectomy (OVX) induced a significant decline in IDE expression in the hippocampus, which was prevented by 17β-E2. Neither OVX nor 17β-E2 affected IDE expression in the cerebellum. In vivo analyses in triple transgenic AD (3xTg-AD) female mice revealed an inverse correlation between the age-related increase in Aβ load and the decrease in IDE expression in the hippocampal formation. Treatment with 17β-E2 attenuated Aβ accumulation/plaque formation and elevated hippocampal IDE expression in 12-month-old 3xTg-AD OVX mice. Collectively, these findings indicate that 17β-E2 regulates IDE expression in a brain region-specific manner and such a regulatory role in the hippocampus, mediated by an ERβ/PI3-K pathway, could serve as a direct mechanism underlying estrogen-mediated preventative effect against AD when initiated at the onset of menopause.

DOI10.1016/j.neurobiolaging.2009.12.010
Alternate JournalNeurobiol. Aging
PubMed ID20053478
PubMed Central IDPMC2889185
Grant ListR01 MH067159-05 / MH / NIMH NIH HHS / United States
R01 AG032236 / AG / NIA NIH HHS / United States
R01 MH067159-04 / MH / NIMH NIH HHS / United States
R01 MH067159 / MH / NIMH NIH HHS / United States
P01 AG026572-04 / AG / NIA NIH HHS / United States
P01 AG026572-030003 / AG / NIA NIH HHS / United States
P01 AG026572 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D