Testosterone reduces neuronal secretion of Alzheimer's β-amyloid peptides
Testosterone reduces neuronal secretion of Alzheimer's β-amyloid peptides
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DOI：
10.1073/pnas.97.3.1202
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发表时间：
2000-02-01
影响因子：
11.1
通讯作者：
Greengard, P
中科院分区：
文献类型：
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作者：
Gouras, GK;Xu, HX;Greengard, P
阿尔茨海默病（AD）的特征是与年龄相关的β -淀粉样蛋白（A β） 40/42肽聚集体在易感脑区域沉积。多个层面的证据表明a β在阿尔茨海默病的病理生理中起着核心作用。β肽是由约700-aa A β前体蛋白（β APP）的调控裂解产生的。全长β - APP可以在A - β结构域内进行蛋白水解裂解，产生分泌的s - β - APP α，也可以在A - β的N端和c端结构域进行蛋白水解裂解，产生淀粉样变性的A - β肽。一些流行病学研究报道，雌激素替代疗法可以防止绝经后妇女发生AD。我们之前报道用17 β -雌二醇处理培养的神经元可减少A β 40/42肽的分泌，这表明雌激素替代疗法可能通过调节β - APP代谢来保护女性免受AD的发展。越来越多的证据表明，睾酮，尤其是生物可利用的睾酮，在老年男性和绝经后妇女中随着年龄的增长而下降。我们在这里报道，睾酮治疗增加了非淀粉样变性APP片段spAPP α的分泌，并减少了N2a细胞和大鼠初级脑皮质神经元A β肽的分泌。这些结果提高了老年男性补充睾酮可能对治疗AD有保护作用的可能性。
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.