Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Exp Mol Med. 2022 Apr;54(4):433-446. doi: 10.1038/s12276-022-00754-8. Epub 2022 Apr 8.
Alzheimer's disease (AD) is caused by synaptic and neuronal loss in the brain. One of the characteristic hallmarks of AD is senile plaques containing amyloid β-peptide (Aβ). Aβ is produced from amyloid precursor protein (APP) by sequential proteolytic cleavages by β-secretase and γ-secretase, and the polymerization of Aβ into amyloid plaques is thought to be a key pathogenic event in AD. Since γ-secretase mediates the final cleavage that liberates Aβ, γ-secretase has been widely studied as a potential drug target for the treatment of AD. γ-Secretase is a transmembrane protein complex containing presenilin, nicastrin, Aph-1, and Pen-2, which are sufficient for γ-secretase activity. γ-Secretase cleaves >140 substrates, including APP and Notch. Previously, γ-secretase inhibitors (GSIs) were shown to cause side effects in clinical trials due to the inhibition of Notch signaling. Therefore, more specific regulation or modulation of γ-secretase is needed. In recent years, γ-secretase modulators (GSMs) have been developed. To modulate γ-secretase and to understand its complex biology, finding the binding sites of GSIs and GSMs on γ-secretase as well as identifying transiently binding γ-secretase modulatory proteins have been of great interest. In this review, decades of findings on γ-secretase in AD are discussed.
阿尔茨海默病（AD）是由大脑中的突触和神经元丧失引起的。AD 的一个特征性标志是含有淀粉样β肽（Aβ）的老年斑。Aβ由淀粉样前体蛋白（APP）通过β-分泌酶和γ-分泌酶的顺序蛋白水解切割产生，Aβ的聚合形成淀粉样斑块被认为是 AD 的关键致病事件。由于 γ-分泌酶介导释放 Aβ 的最终切割，因此 γ-分泌酶已被广泛研究作为治疗 AD 的潜在药物靶点。γ-分泌酶是一种跨膜蛋白复合物，包含早老素、尼卡斯特林、Aph-1 和 Pen-2，这些足以发挥 γ-分泌酶的活性。γ-分泌酶切割超过 140 种底物，包括 APP 和 Notch。先前的研究表明，由于 Notch 信号的抑制，γ-分泌酶抑制剂（GSIs）在临床试验中会引起副作用。因此，需要更特异的调节或调制 γ-分泌酶。近年来，已经开发出 γ-分泌酶调节剂（GSMs）。为了调节 γ-分泌酶并了解其复杂的生物学特性，发现 GSIs 和 GSMs 在 γ-分泌酶上的结合位点以及鉴定瞬时结合 γ-分泌酶调节蛋白一直是人们关注的焦点。在这篇综述中，讨论了几十年来 AD 中 γ-分泌酶的研究发现。
