Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates β-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment

Carrie McAllister, Jiangang Long, Adrienne Bowers, Aaron Walker, Philip Cao, Shin Ichiro Honda, Nobuhiro Harada, Matthias Staufenbiel, Yong Shen, Rena Li

Research output: Contribution to journalArticle

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Abstract

As brain testosterone plays both androgenic and estrogenic actions due to its conversion into estrogen via aromatase naturally, it is unclear that the age-related reduction of testosterone increased risk of Alzheimer's disease (AD) in men is mediated through androgen alone or both androgen and estrogen mechanisms. Our previous studies using a gene-based approach in mouse model to block the conversion of testosterone into estrogen (aromatase gene knock-out, ArKO), found a depletion of estrogen and increase in testosterone endogenously in males. Here, we use crossing the ArKO mice with APP23 transgenic mice, a mouse model of AD, to produce APP23/ Ar+/-mice to study the estrogen-independent effect of testosterone on AD. We found a significant reduction in brain plaque formation, improved cognitive function and increase NEP activity in male APP23/Ar+/- mice compared with age-matched male APP23 controls. In addition, we found, for the first time, a reduction of β-secretase (BACE1) enzyme activity,mRNAlevel and protein expression in the male APP23/Ar+/- mice, suggesting that endogenous testosterone, independent from estrogen, may protect against AD in males via two major mechanisms, downregulation of BACE1 activities at transcriptional level to reduce β amyloid production and upregulation of NEP activities to enhance bate amyloid degradation.

Original languageEnglish (US)
Pages (from-to)7326-7334
Number of pages9
JournalJournal of Neuroscience
Volume30
Issue number21
DOIs
StatePublished - May 26 2010
Externally publishedYes

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Amyloid Precursor Protein Secretases
Aromatase
Amyloid beta-Protein Precursor
Transgenic Mice
Testosterone
Estrogens
Down-Regulation
Pathology
Alzheimer Disease
Gene Knockout Techniques
Amyloid
Androgens
Brain
Knockout Mice
Cognition
Cognitive Dysfunction
Up-Regulation
Enzymes
Genes
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates β-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. / McAllister, Carrie; Long, Jiangang; Bowers, Adrienne; Walker, Aaron; Cao, Philip; Honda, Shin Ichiro; Harada, Nobuhiro; Staufenbiel, Matthias; Shen, Yong; Li, Rena.

In: Journal of Neuroscience, Vol. 30, No. 21, 26.05.2010, p. 7326-7334.

Research output: Contribution to journalArticle

McAllister, Carrie ; Long, Jiangang ; Bowers, Adrienne ; Walker, Aaron ; Cao, Philip ; Honda, Shin Ichiro ; Harada, Nobuhiro ; Staufenbiel, Matthias ; Shen, Yong ; Li, Rena. / Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates β-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 21. pp. 7326-7334.
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AU - Staufenbiel, Matthias

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