Moderate environmental enrichment mitigates tauopathy in a neurofibrillary tangle mouse model.

Epidemiological studies show that stimulating activities reduce the risk of dementia. In animal models of Alzheimer disease, there have been conflicting results of the effects of environmental enrichment (EE) on disease-related amyloid pathology. Here, we tested the direct effect of EE, independently of amyloid pathology, on brain neurofibrillary tangles (NFTs), which best correlate with dementia. We exposed transgenic mice (E257K/P301S-Tau-Tg driven by the natural tau promoter) to moderate nonstrained EE or regular environment. Concomitant with neurogenesis, we detected a decrease in NFT burden and a decrease in the activation of microglia in EE versus regular-environment mice. There was also a trend toward improvement in cognitive tasks in the EE mice. Increased immunoreactivity of brain-derived neurotrophic factor, which is involved in the regulation of tau phosphorylation, was detected in the EE mice, suggesting its possible involvement in the beneficial effects on NFTs and other parameters in the EE mice. These results suggest that NFTs may be directly responsive to environmental stimulating activities and that even nonstrained activities may mitigate tauopathies independent of the involvement of amyloid.