DISCOVERY OF NOVEL GENETIC MODULATORS OF TAU AGGREGATION IN ALZHEIMER’S DISEASE

Tau aggregation is a defining pathological feature of Alzheimer’s disease and related tauopathies. Although tau pathology is tightly associated with neurodegeneration, the genetic determinants that regulate tau aggregation within neurons remain incompletely understood, particularly in the context of disease-relevant cellular environments. To systematically identify genetic modifiers of tau aggregation, we performed a functional CRISPR screening in neuronal models. Genome-wide CRISPR knockout libraries were combined with a tau bimolecular fluorescence complementation (Tau-BiFC) reporter system to enable quantitative assessment of intracellular tau aggregation following genetic perturbation. Integration of primary screening results with secondary validation using individual sgRNAs identified multiple high-confidence genetic regulators that either enhanced or suppressed tau aggregation without affecting overall tau expression. Candidate genes were prioritized based on conserved neuronal expression and relevance to neurodegenerative disease. Mechanistic analyses in human neuron-like cells demonstrated that perturbation of selected candidates alters tau aggregation dynamics, including effects on tau phosphorylation state and aggregation propensity. To evaluate the in vivo relevance of these findings, gene expression was further modulated in animal models via stereotactic delivery of viral vectors into defined brain regions. Targeted genetic manipulation in vivo resulted in corresponding changes in tau pathology, supporting a functional role for selected candidates in regulating tau aggregation within the intact brain. Together, these results define a systematic functional landscape of genetic factors controlling tau aggregation in neurons. Our study provides mechanistic insight into tau pathology and identifies previously unrecognized regulators that may represent potential therapeutic targets for tau-driven neurodegenerative diseases.