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

Insoluble, fibrillar intraneuronal accumulation of the tau protein termed neurofibrillary tangles (NFTs), are characteristic hallmarks of Alzheimer's disease (AD). They play a significant role in the behavioral phenotypes of AD. Certain mice (rTg4510) constitutively express mutant human tau until transgene expression is inactivated by the administration of doxycycline (DOX). The present study aimed to determine the timing of the onset of memory impairment in rTg4510 mice and define the relationship between the extent of memory deficit and the duration of NFT overexpression. In 6-month-old (young) rTg4510 mice, both spatial memory and object recognition memory were impaired. These impairments were prevented by pre-treatment with DOX for 2 months. In parallel, the expression of NFTs decreased in the DOX-treated group. Ten-month-old (aged) rTg4510 mice showed severe impairments in memory performance. Pretreatment with DOX did not prevent these impairments. Increasing levels of NFTs were observed in aged rTg4510 mice. DOX treatment did not prevent tau pathology in aged rTg4510 mice. Expression of the autophagy markers LC3A and LC3B increased in rTg4510 mice, along with an increase in NFT formation. These results suggest that the clearance mechanisms of NFTs are impaired at 10 months of age.