Document Type
Article
Publication Date
12-1-2025
Original Citation
Cary G,
Li Q,
Wiley J,
Paisie C,
Du Y,
Zoeller E,
Duong D,
Fu H,
Seyfried N,
Levey A,
Betarbet R,
Carter GW,
.
Integrated phenotypic and proteomic screening identifies top-tier Alzheimer's disease therapeutic targets. Alzheimers Dement. 2025;21(12):e71008.
Keywords
JGM, JMG, Proteomics, Alzheimer Disease, Animals, Phenotype, Mice, Microglia, Presenilin-2, Humans, RNA, Small Interfering, Cell Line
JAX Source
Alzheimers Dement. 2025;21(12):e71008.
ISSN
1552-5279
PMID
41388808
DOI
https://doi.org/10.1002/alz.71008
Grant
Sun Health Research Institute Brain and Body Donation Program of Sun City; Arizona Alzheimer’s Disease Core Cente; Arizona Department of Health Services; National Institute on Aging, Grant/Award Number: U54 AG065187
Abstract
INTRODUCTION: Alzheimer's 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.
METHODS: We 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 small interfering RNA-mediated perturbations followed by cellular phenotypic assays and quantitative proteomics.
RESULTS: Twenty-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.
DISCUSSION: We established a scalable platform for target functional validation that bridges unbiased systems-level assessments of AD risk with experimental evidence. The Emory-Sage-Structural Genomics Consortium-Jax Center Target Enablement to Accelerate Therapy Development for Alzheimer's Disease center will prioritize further resource development for these validated targets.
HIGHLIGHTS: A screening platform was created to identify the most potent targets from nominated hypotheses. Integrated analysis of cellular proteomics and assay phenotypes was performed. Targets capable of reversing disease-associated proteomic signal were identified. The most impactful targets were strongly implicated in Alzheimer's disease pathogenesis.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.