A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets

Jackson A. Roberts; Vijay R. Varma; Yang An; Sudhir Varma; Julián Candia; Giovanna Fantoni; Vinod Tiwari; Carlos Anerillas; Andrew Williamson; Atsushi Saito; Tina Loeffler; Irene Schilcher; Ruin Moaddel; Mohammed Khadeer; Jacqueline Lovett; Toshiko Tanaka; Olga Pletnikova; Juan C. Troncoso; David A. Bennett; Marilyn S. Albert; Kaiwen Yu; Mingming Niu; Vahram Haroutunian; Bin Zhang; Junmin Peng; Deborah L. Croteau; Susan M. Resnick; Myriam Gorospe; Vilhelm A. Bohr; Luigi Ferrucci; Madhav Thambisetty

doi:10.1126/sciadv.abi8178

A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets

Jackson A. Roberts, Vijay R. Varma, Yang An, Sudhir Varma, Julián Candia, Giovanna Fantoni, Vinod Tiwari, Carlos Anerillas, Andrew Williamson, Atsushi Saito, Tina Loeffler, Irene Schilcher, Ruin Moaddel, Mohammed Khadeer, Jacqueline Lovett, Toshiko Tanaka, Olga Pletnikova, Juan C. Troncoso, David A. Bennett, Marilyn S. AlbertKaiwen Yu, Mingming Niu, Vahram Haroutunian, Bin Zhang, Junmin Peng, Deborah L. Croteau, Susan M. Resnick, Myriam Gorospe, Vilhelm A. Bohr, Luigi Ferrucci, Madhav Thambisetty

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	eabi8178
Journal	Science Advances
Volume	7
Issue number	46
DOIs	https://doi.org/10.1126/sciadv.abi8178
State	Published - Nov 2021

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Roberts, J. A., Varma, V. R., 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, J. C., Bennett, D. A., ... Thambisetty, M. (2021). A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets. Science Advances, 7(46), Article eabi8178. https://doi.org/10.1126/sciadv.abi8178

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 2021, 'A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets', Science Advances, vol. 7, no. 46, eabi8178. https://doi.org/10.1126/sciadv.abi8178

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title = "A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets",

abstract = "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.",

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doi = "10.1126/sciadv.abi8178",

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AU - Varma, Sudhir

AU - Candia, Julián

AU - Fantoni, Giovanna

AU - Tiwari, Vinod

AU - Anerillas, Carlos

AU - Williamson, Andrew

AU - Saito, Atsushi

AU - Loeffler, Tina

AU - Schilcher, Irene

AU - Moaddel, Ruin

AU - Khadeer, Mohammed

AU - Lovett, Jacqueline

AU - Tanaka, Toshiko

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AU - Troncoso, Juan C.

AU - Bennett, David A.

AU - Albert, Marilyn S.

AU - Yu, Kaiwen

AU - Niu, Mingming

AU - Haroutunian, Vahram

AU - Zhang, Bin

AU - Peng, Junmin

AU - Croteau, Deborah L.

AU - Resnick, Susan M.

AU - Gorospe, Myriam

AU - Bohr, Vilhelm A.

AU - Ferrucci, Luigi

AU - Thambisetty, Madhav

N1 - Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets

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