Testosterone reduces neuronal secretion of Alzheimer's β-amyloid peptides

Abstract

Alzheimer's disease (AD) is characterized by the age-related deposition of ␤-amyloid (A␤) 40͞42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for A␤ in the pathophysiology of AD. A␤ peptides are generated by the regulated cleavage of an Ϸ700-aa A␤ precursor protein (␤APP). Full-length ␤APP can undergo proteolytic cleavage either within the A␤ domain to generate secreted s␤APP␣ or at the N-and C-terminal domain(s) of A␤ to generate amyloidogenic A␤ 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 17␤-estradiol reduced the secretion of A␤40͞42 peptides, suggesting that estrogen replacement therapy may protect women against the development of AD by regulating ␤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, s␤APP␣, and decreases the secretion of A␤ 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. A lzheimer's disease (AD) is characterized by the deposition of senile plaques and neurofibrillary tangles in vulnerable brain regions. Senile plaques are composed of aggregated ␤-amyloid (A␤) 40͞42(43) peptides. Evidence implicates a central role for A␤ in the pathophysiology of AD (1). Epidemiological studies have reported that estrogen replacement therapy protects against the development of AD in postmenopausal women (2, 3). We previously reported that treating cultured neurons with 17␤-estradiol reduced the secretion of A␤40͞42 peptides, suggesting that estrogen replacement therapy may protect women against the development of AD by regulating A␤ precursor protein (␤APP) metabolism (4). Although it has long been established that estrogen declines during menopause in aging women, declines in testosterone in aging men, until more recently, have been more controversial. Increasing numbers of reports indicate that testosterone, especially bioavailable free testosterone, declines significantly in aging men (5, 6) and in postmenopausal women (7). Although the relative decrease in the level of testosterone in men is modest compared with those of estrogen in perimenopausal women, aging men develop clinical signs of hypogonadism, such as reduced muscle and bone mass and an increase in visceral fat. Recent studies suggest that declining testosterone levels in older men are associated with disorders similar to those associated with estrogen deficiency in postmenopausal aging women, including osteoporosis (8, 9). Testosterone supplementation in orchiectomized, aging male rats protected these animals from osteoporosis and the decrease in the rate of perios...

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“…Epidemiological studies indicate that AD is more common in females than in males, and the underlying mechanism for this sex difference has been proposed to involve the higher levels of estrogen in females (Manthey et al, 2001;Zhang et al, 2005). Another explanation may be that because males express more testosterone this leads to reduction in levels of Aβ since it has been demonstrated that testosterone reduces Aβ production (Gouras et al, 2000). Interestingly, we found that male 3xTgAD mice exhibited many more tau immunoreactive CA1 and amygdalar neurons compared to females.…”

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