Roberts Jackson A, Varma Vijay R, An Yang, Varma Sudhir, Candia Julián, Fantoni Giovanna, Tiwari Vinod, Anerillas Carlos, Williamson Andrew, Saito Atsushi, Loeffler Tina, Schilcher Irene, Moaddel Ruin, Khadeer Mohammed, Lovett Jacqueline, Tanaka Toshiko, Pletnikova Olga, Troncoso Juan C, Bennett David A, Albert Marilyn S, Yu Kaiwen, Niu Mingming, Haroutunian Vahram, Zhang Bin, Peng Junmin, Croteau Deborah L, Resnick Susan M, Gorospe Myriam, Bohr Vilhelm A, Ferrucci Luigi, Thambisetty Madhav
Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032.
Sci Adv. 2021 Nov 12;7(46):eabi8178. doi: 10.1126/sciadv.abi8178. Epub 2021 Nov 10.
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 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.
基于适配体的蛋白质组学研究揭示了巴尔的摩纵向衰老研究和宗教团体研究中阿尔茨海默病（AD）患者大脑中丰度存在差异的蛋白质（平均年龄89±9岁）。相对于非携带者（平均年龄39±6岁），这些蛋白质中的一部分在年轻的ε4携带者大脑中丰度也存在差异。其中几种蛋白质是其他适应症已获批和实验性药物的靶点，并在独立的人脑组织样本以及转基因AD模型中通过正交方法得到验证。通过基于细胞培养的表型分析，我们发现靶向细胞因子转导蛋白STAT3以及Src家族酪氨酸激酶YES1和FYN的药物挽救了与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。
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