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Vol. 97, Issue 3, 1202-1205, February 1, 2000

Medical Sciences
 Testosterone reduces neuronal secretion of Alzheimer's beta -amyloid peptides

Gunnar K. Gouras*,dagger ,Dagger , Huaxi Xu*,Dagger , Rachel S. Gross*, Jeffrey P. Greenfield*, Bing Hai*, Rong Wang§, and Paul Greengard*,

* Laboratory of Molecular and Cellular Neuroscience and Fisher Center for Research on Alzheimer's Disease, and § Laboratory of Mass Spectrometry, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and dagger  Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021

Contributed by Paul Greengard, December 2, 1999

Alzheimer's disease (AD) is characterized by the age-related deposition of beta -amyloid (Abeta ) 40/42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for Abeta in the pathophysiology of AD. Abeta peptides are generated by the regulated cleavage of an approx 700-aa Abeta precursor protein (beta APP). Full-length beta APP can undergo proteolytic cleavage either within the Abeta domain to generate secreted sbeta APPalpha or at the N- and C-terminal domain(s) of Abeta to generate amyloidogenic Abeta peptides. Several epidemiological studies have reported that estrogen replacement therapy protects against the development of AD in postmenopausal women. We previously reported that treating cultured neurons with 17beta -estradiol reduced the secretion of Abeta 40/42 peptides, suggesting that estrogen replacement therapy may protect women against the development of AD by regulating beta APP metabolism. Increasing evidence indicates that testosterone, especially bioavailable testosterone, decreases with age in older men and in postmenopausal women. We report here that treatment with testosterone increases the secretion of the nonamyloidogenic APP fragment, sbeta APPalpha , and decreases the secretion of Abeta peptides from N2a cells and rat primary cerebrocortical neurons. These results raise the possibility that testosterone supplementation in elderly men may be protective in the treatment of AD.

Dagger G.K.G. and H.X. contributed equally to this work.

To whom reprint requests should be addressed. E-mail: greengd{at}rockvax.rockefeller.edu.


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