Behavioural Functions and Cerebral Blood Flow in a P301S Tauopathy Mouse Model: A Time-Course Study.

Faraz Ahmad,Ping Liu,Yu Jing,Hu Zhang,Hannah Mein

doi:10.3390/ijms22189727

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.

Highlights

Tauopathies refer to a group of neurodegenerative diseases with intracellular accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT)
Aggregation of hyperphosphorylated tau leads to the formation of paired helical filaments, neurofibrillary tangles (NFTs) and other types of fibrillar deposits, the pathological hallmarks of Alzheimer’s disease (AD), frontotemporal dementia (FTD) and other types of tauopathies [1,2]
Earlier research has shown that multiple pathogenic mutations in MAPT are associated with diverse FTD syndromes, and, contribute to frontotemporal lobar degeneration [3]

Summary

Introduction

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. Tauopathies refer to a group of neurodegenerative diseases with intracellular accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT). Earlier research has shown that multiple pathogenic mutations in MAPT are associated with diverse FTD syndromes, and, contribute to frontotemporal lobar degeneration [3]. Both non-transgenic and transgenic animal models of tauopathies are key to understanding the structural, cellular and behavioural effects of abnormal tau. Transgenic mice bearing the MAPT P301 mutation are commonly employed to mimic human frontotemporal lobar degeneration [4,5]. PS19 mice are created by overexpressing a human tau form (with four microtubulebinding domains and one N-terminal insert, 4R/1N) with the Pro301Ser mutation [6,7]

Methods

Results

Conclusion