The authors demonstrate a strategy to rapidly link Alzheimer's disease (AD) risk genes to druggable biological processes using zebrafish. They first identified that around 75% of human AD risk genes have clear orthologues in zebrafish, and most are expressed early in larval brain development.
The authors then developed a high-throughput video-tracking system and analysis pipeline (FramebyFrame) to measure sleep/wake behaviors of zebrafish larvae with F0 knockouts of AD risk genes at high temporal resolution. This revealed distinct behavioral phenotypes for different gene knockouts:
The authors suggest these behavioral changes reflect disruption of specific biological processes that contribute to AD pathogenesis. As proof-of-concept, they showed that sorl1 mutants have disrupted serotonin signaling, and identified betamethasone as a drug that can normalize the sleep phenotype of presenilin-2 knockouts.
This behavioral pharmacology approach provides a general framework to rapidly link disease-associated genes to druggable pathways, which could accelerate the discovery of new therapeutic targets.
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by Krol... às www.biorxiv.org 11-29-2023
https://www.biorxiv.org/content/10.1101/2023.11.28.568940v1Perguntas Mais Profundas