Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129-2060, USA; Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen 9747 AG, The Netherlands.
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129-2060, USA.
EBioMedicine. 2017 Oct;24:93-101. doi: 10.1016/j.ebiom.2017.08.028. Epub 2017 Sep 4.
A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aβ42 levels without affecting either α- and β-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.
阿尔茨海默病（AD）的一个中心致病事件是 Aβ42 肽的积累，该肽通过β-和γ-分泌酶的切割从淀粉样前体蛋白（APP）中产生。我们开发了一类可溶性 2-氨基噻唑 γ-分泌酶调节剂（SGSM），它们优先降低 Aβ42 水平。然而，SGSM 在表达家族性 AD 突变的 AD 动物和细胞中的作用以及 γ-分泌酶调节的机制在很大程度上仍然未知。在这里，使用表达 FAD 突变的动物和细胞研究了该 SGSM 支架的代表性化合物 SGSM-36。SGSM-36 优先降低 Aβ42 水平，而不影响 APP 的 α-和 β-分泌酶加工或 Notch 加工。此外，在 γ-分泌酶复合物内鉴定出一个变构位点，允许使用基于细胞的荧光寿命成像显微镜分析来进入 SGSM-36。总之，这些研究提供了有关该类 SGSM 的机制见解，并增强了它们在 AD 中的治疗潜力。
