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

Alzheimer's disease (AD) is characterized by the age-related deposition of beta-amyloid (A beta) 40/42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for A beta in the pathophysiology of AD. A beta peptides are generated by the regulated cleavage of an approximate to 700-aa A beta precursor protein (beta APP). Full-length beta APP can undergo proteolytic cleavage either within the A beta domain to generate secreted s beta APP alpha or at the N- and C-terminal domain(s) of A beta to generate amyloidogenic A beta 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 beta-estradiol reduced the secretion of A beta 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, spAPP alpha, and decreases the secretion of A beta 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.