Understanding Tau pathology: insights from animal models

Tauopathies encompass a group of neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), Pick’s disease (PiD), corticobasal degeneration (CBD), which are characterized by tau protein dysfunction and insoluble tau accumulation inside the neurons. During pathogenesis, hyperphosphorylation of tau leads to its aggregation into neurofibrillary tangles (NFTs), which are spatially and functionally tightly linked to neurodegenerative changes as well as the progression of clinical symptoms. A plethora of transgenic mouse models with wild-type or mutant human TAU has been generated to uncover the molecular mechanisms of tauopathies. Considerable progress has been made in tau research has been supported by these rodent models, recent clinical trials of tau-targeting therapies have failed to produce clinical benefits. The limited success of tau-targeted therapies has raised significant concerns about the precise mechanism underlying tauopathies and the fidelity of animal models in evaluating therapeutic targets. In this review, we comprehensively analyze the phenotypes, underlying pathological features, and molecular mechanisms across different rodents and non-human primates (NHPs) tauopathy models. Additionally, we outline the advantages, limitations, and inherent challenges of the preclinical models so that offer valuable references for the effective development of clinical therapeutic strategies.