Understanding Tau pathology: Insights from animal models.

Abstract

Tauopathies represent a class of neurodegenerative diseases (NDs), including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Pick's disease (PiD), and corticobasal degeneration (CBD), defined by intracellular accumulation of misfolded and hyperphosphorylated tau protein. The pathogenic cascade involves hyperphosphorylation, conformational changes, and aggregation into neurofibrillary tangles (NFTs), which are spatially and functionally linked to neuronal dysfunction, synaptic loss, and progressive cognitive and motor decline. To elucidate tau-mediated mechanisms, diverse transgenic rodent models expressing wild-type or mutant forms of human TAU have been generated. Although these models have advanced understanding of tau aggregation and propagation, tau-targeting therapies have failed to produce clinical benefits, raising concerns about the precise mechanism underlying tauopathies and the fidelity of animal models in evaluating therapeutic targets. This review systematically examines the neuropathological and behavioral phenotypes across established rodent and non-human primate (NHP) tauopathy models, highlighting mechanistic insights into tau-driven pathology. The advantages, limitations, and translational barriers of each model are critically evaluated to inform the development of more predictive preclinical platforms for therapeutic discovery.