Understanding Tau pathology: Insights from animal models

Area of Science:

• Neuroscience
• Pathology
• Pharmacology

Background:

• Tauopathies are neurodegenerative diseases characterized by the accumulation of misfolded tau protein, leading to neuronal dysfunction and cognitive decline.
• Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Pick's disease (PiD), and corticobasal degeneration (CBD) are key examples of tauopathies.
• The intracellular aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs) is a hallmark of these conditions.

Purpose of the Study:

• To systematically review neuropathological and behavioral phenotypes in rodent and non-human primate (NHP) models of tauopathies.
• To provide mechanistic insights into tau-driven pathology using these models.
• To critically evaluate the advantages, limitations, and translational barriers of current tauopathy models.

Main Methods:

• Systematic examination of neuropathological and behavioral data from established rodent and NHP tauopathy models.
• Critical evaluation of model fidelity in representing human tauopathies.
• Analysis of translational barriers in preclinical models for therapeutic discovery.

Main Results:

• Existing transgenic models have advanced understanding of tau aggregation and propagation.
• Despite model advancements, tau-targeting therapies have shown limited clinical success, suggesting potential discrepancies between models and human disease.
• Significant limitations and translational barriers exist in current animal models for evaluating tau-targeting therapies.

Conclusions:

• Current rodent and NHP models offer valuable insights but have limitations in fully recapitulating human tauopathies.
• The failure of tau-targeting therapies highlights the need for more predictive preclinical models.
• Further refinement and critical evaluation of animal models are essential for advancing therapeutic discovery in neurodegenerative diseases.