Age-dependent impairment of memory, neurofibrillary tangle formation and clearance in a mouse model of tauopathy

Insoluble, fibrillar intraneuronal accumulations of the tau protein called neurofibrillary tangles (NFTs) are important hallmarks of the Alzheimer disease (AD) brain and play an important role in the behavioral phenotypes of AD. rTg4510 mice constitutively express mutant human tau until transgene expression is inactivated by administration of the doxycycline (DOX). The present study aimed to determine the initial phenotypic characterization of the rTg4510 mice and to define the relationship between the extent of memory deficit and the duration of NFTs overexpression. In 6-month-old (young) rTg4510 mice, both spatial memory and object recognition memory ware impaired, and these impairments were recovered by pre-treatment with DOX for 2 months. In parallel, the expression of NFTs decreased in DOX treated group. 10-month-old (aged) rTg4510 mice showed strict impairment in memory performances and treatment with DOX could not recover these impairments. Increasing levels of NFTs were observed in aged rTg4510 mice. Treatment with DOX could not recover the tau pathology in aged rTg4510 mice as well as DOX-untreated group. These results suggest that clearance mechanisms of NFTs were impaired as of 10 months of age.