Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

Richard L. Bowen, Giuseppe Verdile, Tianbing Liu, Albert F. Parlow, George Perry, Mark A. Smith, Ralph N. Martins, Craig S. Atwood*

*Corresponding author for this work

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Hormonal changes associated with the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause/andropause have been implicated in the pathogenesis of Alzheimer's disease (AD). Experimental support for this has come from studies demonstrating an increase in amyloid-β (Aβ) deposition following ovariectomy/castration. Because sex steroids and gonadotropins are both part of the HPG feedback loop, any loss in sex steroids results in a proportionate increase in gonadotropins. To assess whether Aβ generation was due to the loss of serum 17β-estradiol or to the up-regulation of serum gonadotropins, we treated C57B1/6J mice with the anti-gonadotropin leuprolide acetate, which suppresses both sex steroids and gonadotropins. Leuprolide acetate treatment resulted in a 3.5-fold (p < 0.0001) and a 1.5-fold (p < 0.024) reduction in total brain Aβ1-42 and Aβ1-40 concentrations, respectively, after 8 weeks of treatment. To further explore the role of gonadotropins in promoting amyloidogenesis, M17 neuroblastoma cells were treated with the gonadotropin luteinizing hormone (LH) at concentrations equivalent to early adulthood (10 mIU/ml) or post-menopause/andropause (30 mIU/ml). LH did not alter amyloid-β precursor protein (AβPP) expression but did alter AβPP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of Aβ, decreased αAβPP secretion, and increased AβPP-C99 levels. These results suggest the marked increases in serum LH following menopause/andropause as a physiologically relevant signal that could promote Aβ secretion and deposition in the aging brain. Suppression of the age-related increase in serum gonadotropins using anti-gonadotropin agents may represent a novel therapeutic strategy for AD.

Original languageEnglish
Pages (from-to)20539-20545
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number19
DOIs
Publication statusPublished - 7 May 2004
Externally publishedYes

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