A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies 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 ε4 carriers relat...

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Published in:Science advances 2021-11, Vol.7 (46), p.eabi8178
Main Authors: 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
Format: Article
Language:English
Subjects:
Neuroscience
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abi8178