From the Department of Neurobiology and Behavior Institute for Memory Impairments and Neurological Disorders, University of California at Irvine, Irvine, CA 92697-4545, USA.
Ann Neurol. 2011 May;69(5):831-44. doi: 10.1002/ana.22325. Epub 2011 Mar 17.
Inhibiting Aβ generation is a prime therapeutic goal for preventing or treating Alzheimer disease. Here we sought to identify any disease-modifying properties of an azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-idan]-2(3H)-one (ST101 or ZSET1446).
The effects of ST101 were studied in 3xTg-AD mice and young cynomolgus monkeys using a combination of biochemical and histological analyses.
Here we describe that ST101 induces cleavage of APP protein at a novel site, generating a 17 kDa C-terminal fragment. This 17 kDa APP cleavage product does not appear to be a substrate for either α- or β-secretase, and thus bypasses generation of Aβ. ST101 is orally active, efficacious at low doses, improves memory function, and robustly reduces brain Aβ in transgenic mice and nonhuman primates.
Using rodent and nonhuman primate models, we show that ST101 represents a novel class of small molecules that reduce central nervous system levels of Aβ by inducing an alternate pathway of APP cleavage.
抑制 Aβ 的产生是预防或治疗阿尔茨海默病的主要治疗目标。在这里，我们试图确定一种氮茚并吲哚酮衍生物（螺[咪唑并[1,2-a]吡啶-3,2-亚基]-2（3H）-酮（ST101 或 ZSET1446）是否具有疾病修饰特性。
使用生化和组织学分析相结合的方法，在 3xTg-AD 小鼠和年轻食蟹猴中研究 ST101 的作用。
在这里，我们描述了 ST101 在 APP 蛋白的一个新位点诱导切割，产生 17 kDa 的 C 端片段。这种 17 kDa 的 APP 切割产物似乎不是 α-或 β-分泌酶的底物，因此绕过了 Aβ的产生。ST101 具有口服活性，低剂量有效，可改善记忆功能，并在转基因小鼠和非人灵长类动物中强烈降低大脑中的 Aβ。
使用啮齿动物和非人灵长类动物模型，我们表明 ST101 代表了一类通过诱导 APP 切割的替代途径来降低中枢神经系统 Aβ 水平的新型小分子。
