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

摘要

Alzheimer＇s disease (AD) is characterized by the age-related dep- osition 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 prateolytic cleavage either within the Aβ domain to generate secreted sβAPPα or at the N- and C-terminal domain(s) of Aβ to generate amyloidogenic Aβ pep- tides. Several epidemiological studies have reported that estrogen replacement therapy protects against the development of AD in postmenapausal women. We previously reported that treating cultured neurans with 17β-estradial 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 treat- ment with testosterone increases the secretion of the nonamyloi- dogenic 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 supplementa- tion in elderly men may be protective in the treatment of AD.