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Twenty years of therapeutic development in tauopathy mouse models: a scoping review
Vanessa F Langness1, Danielle A Simmons1, Tyne L M McHugh1,2,3
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA.
Abstract:
Tauopathies are neurodegenerative diseases characterized by pathological tau protein inclusions and dementia. Tauopathy mouse models with MAPT mutations replicate tau-related pathologies and are widely used for therapeutic research. This scoping review examines 409 treatment evaluations in MAPT mouse models. We identify trends in therapeutic strategies and frequently used mouse models, treatment routes, and endpoints. We also document treatment effects and when treatment is initiated relative to tau pathology emergence. Many treatments produced positive effects in multiple MAPT mouse models across many endpoints but showed limited success in clinical trials. Potential barriers to mouse-to-human translation include differences between mouse and human studies in the timing of treatment initiation relative to tau pathology onset, predominant testing of a limited number of endpoints, lack of translatable treatment response biomarkers, and the limited ability of individual mouse models to represent the diversity of tauopathies. Addressing these obstacles could improve mouse-to-human translation for tauopathy therapeutics. HIGHLIGHTS: Two decades of therapeutic research in tauopathy mouse models were reviewed. Treatments often began before or at tau pathology onset in tauopathy mouse models. Key endpoints (e.g., cognition and synaptic degeneration) were underassessed. Well-characterized preclinical treatments often had limited success in humans. Single-sex mouse studies and a lack of biomarkers hinder clinical translation.
Insights
Therapeutic strategies for tauopathies (diseases of tau protein pathology) in mouse models often show promise but face translation challenges. Differences in treatment timing and endpoint assessment between mice and humans limit clinical success.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Tauopathies are neurodegenerative disorders defined by abnormal tau protein aggregation and cognitive decline.
- MAPT (MAPT gene) mutations in mouse models are crucial for studying tauopathies and evaluating potential treatments.
- A significant body of research has utilized these models to explore therapeutic interventions.
Purpose of the Study:
- To conduct a comprehensive scoping review of therapeutic interventions tested in MAPT (MAPT gene) mutation tauopathy mouse models.
- To identify trends in therapeutic strategies, model selection, administration routes, and outcome measures.
- To analyze treatment efficacy and the timing of intervention relative to disease onset.
Main Methods:
- Systematic search and review of 409 treatment evaluations in MAPT mouse models.
- Analysis of therapeutic approaches, mouse models used, delivery methods, and assessed endpoints.
- Evaluation of treatment effects and correlation with the initiation of treatment concerning tau pathology.
Main Results:
- Many tested treatments demonstrated positive effects in multiple MAPT mouse models across various endpoints.
- Interventions were frequently initiated before or at the onset of tau pathology in preclinical studies.
- Key endpoints like cognitive function and synaptic degeneration were often underassessed, and single-sex studies were common.
Conclusions:
- Despite preclinical success, many tauopathy therapeutics show limited efficacy in human clinical trials.
- Discrepancies in treatment timing, endpoint evaluation, biomarker use, and model limitations pose barriers to mouse-to-human translation.
- Improving preclinical study designs, including diverse endpoints and biomarkers, is essential for advancing tauopathy therapeutics.
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