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

Alzheimer's disease (AD) is characterized by the age-related deposition of β-amyloid (Aβ) 40/42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for Aβ in the pathophysiology of AD. Aβ peptides are generated by the regulated cleavage of an ≃700-aa Aβ precursor protein (βAPP). Full-length βAPP can undergo proteolytic cleavage either within the A β domain to generate secreted sβAPPα or at the N- and C-terminal domain(s) of Aβ to generate amyloidogenic Aβ 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 17β-estradiol reduced the secretion of Aβ40/42 peptides, suggesting that estrogen replacement therapy may protect women against the development of AD by regulating βAPP 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, sβAPPα, and decreases the secretion of Aβ 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.