GONADAL HORMONES CONTROL BRAIN LEVELS OF ALZHEIMER'S BETA-AMYLOID IN ANIMALS AND PLASMA BETA-AMYLOID LEVELS IN HUMANS
S. Gandy, S. Petanceska, D. Frail, L. Flicker, J. Fonte, O. Almeida, R. Martins
New York University, Nathan Kline Institute, Orangeburg NY and The Sir James McCusker Alzheimer Research Unit of Hollywood Private Hospital, The University of Western Australia, Perth WA.
Fourteen out of fifteen epidemiological studies performed since 1990 indicate that hormone replacement therapy (HRT) can reduce the relative risk of Alzheimer's disease (AD) in postmenopausal women by about one-half (Henderson, Novartis Foundation Symposium Proceedings, 2000). Genotype-phenotype relationships indicate that accumulation in brain of the beta-amyloid peptide is a common initiating factor in genetic forms of AD (Selkoe, Nature, 1999). We hypothesized that HRT might modulate AD risk through hormonal control of beta-amyloid metabolism. We tested this hypothesis by examining the effect of castration on beta-amyloid levels in the brains of experimental animals and in the plasma of human males. When compared to appropriate controls, brain levels of beta-amyloid-(40) and -(42) were increased by 50% in guinea pigs subjected to ovariectomy (Petanceska et al., Neurology, 2000). Brain levels of beta-amyloid returned toward control values when ovariectomized guinea pigs were treated orally with 1 or 5 mg/kg/day 17-beta-estradiol (Petanceska et al., Neurology, 2000). In view of the recent discovery that elevated plasma levels of beta-amyloid are apparently associated with increased risk for AD (Ertekin-Taner et al., Science, 2000), we recently extended these studies to humans. Among six men undergoing chemical androgen suppression therapy for prostate cancer, plasma levels of beta-amyloid roughly doubled (p<0.01) in association with declining levels of circulating testosterone and estrogen. These data suggest that gonadal hormones control beta-amyloid levels in vivo in experimental animals and in humans and support the notion that HRT might delay or prevent AD by lowering brain and plasma levels of Alzheimer's beta-amyloid.
Key words:
Alzheimer's disease, amyloid, hormone, estrogen, testosterone
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