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J. Biol. Chem., Vol. 279, Issue 19, 20539-20545, May 7, 2004

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

From the ^aVoyager Pharmaceutical Corporation, Raleigh, North Carolina 27615, the ^cCentre for Aging and Alzheimer's Disease, School of Biomedical and Sports Science, Edith Cowan University, Joondalup, Western Australia 6027, Australia, the ^dDepartment of Psychiatry and Clinical Neurosciences, The University of Western Australia and The Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia 6009, Australia, the ^eDepartment of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53705, the ^fNational Hormone and Peptide Program, Harbor-UCLA Medical Center, Torrance, California 90509, the ^gInstitute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, and the ^hDepartment of Medicine, University of Wisconsin, Madison, Wisconsin 53705

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- (A) 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 A generation was due to the loss of serum 17-estradiol or to the up-regulation of serum gonadotropins, we treated C57Bl/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 A1-42 and A1-40 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- precursor protein (APP) expression but did alter APP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of A, decreased APP secretion, and increased APP-C99 levels. These results suggest the marked increases in serum LH following menopause/andropause as a physiologically relevant signal that could promote A 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.

Received for publication, November 3, 2003 , and in revised form, February 8, 2004.

^* This work was supported by National Institute of Health Grant RO1-AG19356 and Voyager Pharmaceutical Corporation (to C. S. A.) and by The McCusker Foundation for Alzheimer's Disease Research (to R. N. M.). Drs. Perry, Smith, and Atwood are consultants of Voyager Pharmaceutical Corporation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b Both authors contributed equally to this work.

ⁱ To whom correspondence should be addressed: Dept. of Medicine, University of Wisconsin-Madison and William S. Middleton Memorial VA Hospital (GRECC 11G), 2500 Overlook Terrace, Madison, WI 53705. Tel.: 608-256-1901 (ext. 11664); Fax: 608-280-7291; E-mail: csa{at}medicine.wisc.edu.

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