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Androgens regulate neprilysin expression: role in reducing beta-amyloid levels.
Mingzhong Yao1, Thuy-Vi V Nguyen, Emily R Rosario
1Davis School of Gerontology, University of Southern California, Los Angeles, California 90089-0191, USA.
Journal of Neurochemistry
|March 19, 2008
Summary
Low testosterone (androgen) levels increase Alzheimer's risk. This study shows androgens boost neprilysin (NEP), an enzyme that clears beta-amyloid (Abeta), via androgen receptors (AR).
Area of Science:
- Neuroendocrinology
- Molecular Neuroscience
- Alzheimer's Disease Pathogenesis
Background:
- Age-related testosterone depletion is a risk factor for Alzheimer's disease (AD).
- Androgens' role in AD risk is linked to beta-amyloid protein (Abeta) accumulation via an unknown mechanism.
- Neprilysin (NEP) is an enzyme that catabolizes Abeta.
Purpose of the Study:
- To investigate the role of neprilysin (NEP) in androgen-mediated regulation of Abeta.
- To elucidate the mechanism by which androgens influence Abeta levels.
Main Methods:
- Assessed androgen regulation of NEP expression in rat neural tissues.
- Utilized cultured hippocampal neurons and differentiated pheochromocytoma cells (PC12) with/without androgen receptor (AR).
- Administered dihydrotestosterone (DHT) and measured NEP expression and Abeta levels; employed NEP inhibition and AR antagonists.
Main Results:
- Androgens positively regulate neural NEP expression in rats.
- DHT increased NEP expression and decreased Abeta levels in AR-expressing cells.
- DHT's effects on NEP and Abeta were dependent on AR expression and blocked by AR antagonists and NEP inhibition.
Conclusions:
- Androgen regulation of Abeta involves an AR-dependent pathway.
- This pathway requires the up-regulation of the Abeta-catabolizing enzyme NEP.
- Findings suggest a potential therapeutic target for AD related to androgen signaling and NEP activity.
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