gamma-secretase as a therapeutic target for treatment of Alzheimer's disease.
gamma-secretase as a therapeutic target for treatment of Alzheimer's disease.
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DOI：
10.2174/138161206775474206
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发表时间：
2006-01
影响因子：
3.1
通讯作者：
T. Tomita;T. Iwatsubo
中科院分区：
文献类型：
--
作者：
T. Tomita;T. Iwatsubo
阿尔茨海默病（AD）是伴随衰老的痴呆的最常见原因，其病理特征在于含有淀粉样β肽（Abeta）的老年斑和由磷酸化tau组成的神经元缠结。遗传学和生物学研究提供的证据表明，Abeta的产生和沉积有助于AD的病因学。γ-分泌酶是产生Abeta的C末端的关键酶，其决定了Abeta的聚集性和沉积倾向。通过抑制γ-分泌酶活性调节Abeta产生的药物可以为AD提供有效的治疗方法，尽管最近的研究表明γ-分泌酶在胚胎发育中发挥重要作用的新信号通路中起重要作用。本文综述了γ-分泌酶生物学的最新进展，阐明了这种不寻常的酶的蛋白水解机制，调节和组成。此外，我们还回顾了抑制剂的最新进展，并为通过抑制γ-分泌酶活性有效治疗AD提供了方向。
Alzheimer's disease (AD) is the most common cause of dementia with aging, that is pathologically characterized by senile plaques that contain amyloid-beta peptides (Abeta) and neurofibrillary tangles comprised of phosphorylated tau. Genetic and biological studies provide evidence that the production and deposition of Abeta contribute to the etiology of AD. gamma-Secretase is the pivotal enzyme in generating the C terminus of Abeta, that determines its aggregability and propensity for deposition. Drugs that regulate the production of Abeta by inhibiting gamma-secretase activity could provide an effective therapeutics for AD, although recent studies suggest that gamma-secretase plays important roles in novel signaling pathways that play essential roles in embryonic development. This review focuses on recent progresses in the gamma-secretase biology that shed substantial light on the proteolytic mechanism, regulation and composition of this unusual enzyme. Moreover, we review the recent development of inhibitors and provide a direction for the effective treatment of AD through inhibition of gamma-secretase activity.