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Behavioural Functions and Cerebral Blood Flow in a P301S Tauopathy Mouse Model: A Time-Course Study
Faraz Ahmad1, Hannah Mein1, Yu Jing1
1Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand.
Abstract:
Tauopathies refer to a group of neurodegenerative diseases with intracellular accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) in neurons and glial cells. PS19 mice bearing the MAPT P301S mutation have been used to mimic human frontotemporal lobar degeneration. The present study was designed to systematically investigate how behavioural functions, resting cerebral blood flow (CBF) and tau pathology change in PS19 mice at 2, 4, 6, 8 and 12 months of age in a single study under one experimental condition, allowing for the cumulative assessment of age- and genotype-dependent changes. PS19 mice displayed hyperactivity and reduced anxiety levels with age, early and persistent spatial working memory deficits and reduced resting neocortical CBF. Immunoblotting and immunohistochemistry revealed age-related increases in phosphorylated tau in the brain of PS19 mice. In conclusion, the present study, for the first time, cumulatively demonstrated the time-course of changes in behavioural functions, resting CBF and tau pathology in a P301S tauopathy mouse model through their developmental span. This information provides further evidence for the utility of this model to study neurodegenerative events associated with tauopathy and tau dysfunction.
Insights
This study tracked changes in behavior, brain blood flow, and tau pathology in P301S mice modeling frontotemporal lobar degeneration. Findings reveal age-dependent alterations, supporting this model for tauopathy research.
Area of Science:
- Neuroscience
- Pathology
- Genetics
Background:
- Tauopathies are neurodegenerative diseases characterized by abnormal tau protein accumulation.
- PS19 mice with the MAPT P301S mutation serve as a model for human frontotemporal lobar degeneration.
- Understanding the temporal progression of pathology and associated functional changes is crucial for developing effective treatments.
Purpose of the Study:
- To systematically investigate age- and genotype-dependent changes in behavioral functions, cerebral blood flow (CBF), and tau pathology in PS19 mice.
- To provide a cumulative assessment of these changes across the lifespan of the P301S tauopathy mouse model.
- To evaluate the utility of the PS19 mouse model for studying neurodegenerative events.
Main Methods:
- PS19 mice and control littermates were assessed at multiple ages (2, 4, 6, 8, and 12 months).
- Behavioral functions were evaluated, including measures of activity, anxiety, and spatial working memory.
- Resting cerebral blood flow (CBF) was measured, and brain tissue was analyzed for phosphorylated tau using immunoblotting and immunohistochemistry.
Main Results:
- PS19 mice exhibited age-dependent hyperactivity and reduced anxiety.
- Early and persistent spatial working memory deficits were observed in PS19 mice.
- A reduction in resting neocortical CBF and an age-related increase in phosphorylated tau were detected in PS19 mice.
Conclusions:
- The study provides the first cumulative timeline of behavioral, CBF, and tau pathology changes in the P301S mouse model.
- These findings highlight the progressive nature of tauopathy in this model.
- The PS19 mouse model is validated as a valuable tool for investigating tauopathy and tau dysfunction.
