A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets.
A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets.
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DOI：
10.1126/sciadv.abi8178
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发表时间：
2021-11-12
期刊：
影响因子：
13.6
通讯作者：
Thambisetty M
中科院分区：
文献类型：
--
作者：
Roberts JA;Varma VR;An Y;Varma S;Candia J;Fantoni G;Tiwari V;Anerillas C;Williamson A;Saito A;Loeffler T;Schilcher I;Moaddel R;Khadeer M;Lovett J;Tanaka T;Pletnikova O;Troncoso JC;Bennett DA;Albert MS;Yu K;Niu M;Haroutunian V;Zhang B;Peng J;Croteau DL;Resnick SM;Gorospe M;Bohr VA;Ferrucci L;Thambisetty M
几十年后，年轻的 APOE ε4 携带者的脑蛋白发生改变，在阿尔茨海默病中被发现，并成为新的药物靶点。巴尔的摩老龄化纵向研究和宗教秩序研究（平均年龄，89 ± 9 岁）中基于适体的蛋白质组学揭示了阿尔茨海默病 (AD) 大脑中蛋白质丰度的差异。相对于非携带者（平均年龄，39 ± 6 岁），年轻 APOE ε4 携带者的大脑中这些蛋白质的子集也存在差异。其中一些蛋白质代表了用于其他适应症的已批准和实验药物的靶点，并使用正交方法在独立的人脑组织样本以及转基因 AD 模型中进行了验证。使用基于细胞培养的表型测定，我们发现针对细胞因子转导器 STAT3 和 Src 家族酪氨酸激酶 YES1 和 FYN 的药物可以挽救与 AD 发病机制相关的分子表型。我们的研究结果可能会加速针对 AD 最早分子触发因素的有效干预措施的开发。
Brain proteins altered in young APOE ε4 carriers are found decades later in Alzheimer’s disease and present novel drug targets. Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer’s disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 ± 9 years). A subset of these proteins was also differentially abundant in the brains of young APOE ε4 carriers relative to noncarriers (mean age, 39 ± 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture–based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD.
影响因子：
3.4
作者：
Xing S;Shen D;Chen C;Wang J;Yu Z
通讯作者：
Yu Z