Seizure resistance without parkinsonism in aged mice after tau reduction

Tau is an emerging target for Alzheimer's disease (AD) and other conditions with epileptiform activity. Genetic tau reduction (in Tau(+/-) and Tau(-/-) mice) prevents deficits in AD models and has an excitoprotective effect, increasing resistance to seizures, without causing apparent neuronal dysfunction. However, most studies of tau reduction have been conducted in <1-year-old mice, and the effects of tau reduction in aged mice are less clear. Specifically, whether the excitoprotective effects of tau reduction persist with aging is unknown and whether tau reduction causes neuronal dysfunction, including parkinsonism, with aging is controversial. Here, we performed a comprehensive analysis of 2-year-old Tau(+/+), Tau(+/-), and Tau(-/-) mice. In aged mice, tau reduction still conferred resistance to pentylenetetrazole-induced seizures. Moreover, tau reduction did not cause parkinsonian abnormalities in dopamine levels or motor function and did not cause iron accumulation or impaired cognition, although Tau(-/-) mice had mild hyperactivity and decreased brain weight. Importantly, the excitoprotective effect in aged Tau(+/-) mice was not accompanied by detectable abnormalities, indicating that partially reducing tau or blocking its function may be a safe and effective therapeutic approach for AD and other conditions with increased excitability.