Integrated phenotypic and proteomic screening identifies top-tier Alzheimer's disease therapeutic targets

Cary, G. A.; Li, Q.; Wiley, J. C.; Paisie, C. A.; Du, Y.; Zoeller, E. L.; Duong, D.; Fu, H.; Seyfried, N. T.; Levey, A. I.; Betarbet, R.; Carter, G. W.

doi:10.1101/2025.10.16.682926

bioRxiv · 10.1101/2025.10.16.682926

Integrated phenotypic and proteomic screening identifies top-tier Alzheimer's disease therapeutic targets

Cary, G. A.·Li, Q.·Wiley, J. C.·Paisie, C. A.·Du, Y.·Zoeller, E. L.·Duong, D.·Fu, H.·Seyfried, N. T.·Levey, A. I.·Betarbet, R.·Carter, G. W.

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Abstract

IntroductionAlzheimers disease (AD) is a complex neurodegenerative disorder. Hundreds of therapeutic targets have been nominated through genetic and multi-omic studies, but effective prioritization remains a major bottleneck. MethodsWe applied an integrative screening framework to assess 29 candidate targets from risk-enriched biological domains. Using disease-relevant murine BV2 microglial cell lines with stable Psen2 knockdown, we performed siRNA-mediated perturbations followed by cellular phenotypic assays and quantitative proteomics. ResultsTwenty-five candidate targets significantly altered at least one phenotype, with stronger effects in Psen2 knockdown cells. Integrated proteomic analyses identified several perturbations that reversed AD-associated molecular patterns. Five targets--Ap2a2, Pdhb, Pdha1, Dlat, and Psmc3-- impacted both phenotypes and related proteomic responses. DiscussionWe established a scalable platform for target functional validation that bridges unbiased systems-level assessments of AD risk with experimental evidence. The ESSJ TREAT-AD center will prioritize further resource development for these validated targets.

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Cary, G. A., Li, Q., Wiley, J. C., Paisie, C. A., Du, Y., Zoeller, E. L., Duong, D., Fu, H., Seyfried, N. T., Levey, A. I., Betarbet, R., Carter, G. W.. 2025-10-16. Integrated phenotypic and proteomic screening identifies top-tier Alzheimer's disease therapeutic targets. https://doi.org/10.1101/2025.10.16.682926

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