Somatostatin regulates brain amyloid β peptide Aβ42 through modulation of proteolytic degradation
Somatostatin regulates brain amyloid β peptide Aβ42 through modulation of proteolytic degradation
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DOI：
10.1038/nm1206
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发表时间：
2005-04-01
期刊：
影响因子：
82.9
通讯作者：
Saido, TC
中科院分区：
文献类型：
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作者：
Saito, T;Iwata, N;Saido, TC
在包括猿和人类在内的各种哺乳动物中，大脑中生长抑素的表达在衰老过程中下降（1，2）。这种神经肽的显著减少也代表了阿尔茨海默病的病理特征（3，4）。使用在体外和体内的范例，我们表明，生长抑素调节淀粉样β肽（A β），阿尔茨海默病的主要病原体，在大脑中，通过调节蛋白水解酶催化的降解代谢。在各种效应候选人中，只有生长抑素上调原代皮层神经元中的脑啡肽酶活性。生长抑素的遗传缺陷改变了海马脑啡肽酶的活性和定位，并增加了A β的疏水性42聚体形式A β的数量（42），其方式与导致家族性阿尔茨海默病的早老素基因突变相似。这些结果表明，衰老诱导的生长抑素表达下调可能是A β积累导致迟发性散发性阿尔茨海默病的触发因素，并表明生长抑素受体可能是预防和治疗阿尔茨海默病的药理学靶点候选者。
Expression of somatostatin in the brain declines during aging in various mammals including apes and humans(1,2). A prominent decrease in this neuropeptide also represents a pathological characteristic of Alzheimer disease(3,4). Using in vitro and in vivo paradigms, we show that somatostatin regulates the metabolism of amyloid beta peptide (A beta), the primary pathogenic agent of Alzheimer disease, in the brain through modulating proteolytic degradation catalyzed by neprilysin. Among various effector candidates, only somatostatin upregulated neprilysin activity in primary cortical neurons. A genetic deficiency of somatostatin altered hippocampal neprilysin activity and localization, and increased the quantity of a hydrophobic 42-mer form of A beta, A beta(42), in a manner similar to presenilin gene mutations that cause familial Alzheimer disease. These results indicate that the aging-induced downregulation of somatostatin expression may be a trigger for A beta accumulation leading to late-onset sporadic Alzheimer disease, and suggest that somatostatin receptors may be pharmacological-target candidates for prevention and treatment of Alzheimer disease.