Genetic ablation of tau improves mitochondrial function and cognitive abilities in the hippocampus

Abstract Tau is a key protein for microtubule stability; however, post-translationally modified tau contributes to neurodegenerative diseases by forming tau aggregates in the neurons. Previous reports from our group and others have shown that pathological forms of tau are toxic and impair mitochondrial function, whereas tau deletion is neuroprotective. However, the effects of tau ablation on brain structure and function in young mice have not been fully elucidated. Therefore, the aim of this study was to investigate the implications of tau ablation on the mitochondrial function and cognitive abilities of a litter of young mice (3 months old). Our results showed that tau deletion had positive effects on hippocampal cells by decreasing oxidative damage, favoring a mitochondrial pro-fusion state, and inhibiting mitochondrial permeability transition pore (mPTP) formation by reducing cyclophilin D (Cyp-D) protein. More importantly, tau deletion increased ATP production and improved the recognition memory and attentive capacity of juvenile mice. Therefore, the absence of tau enhanced brain function by improving mitochondrial health, which supplied more energy to the synapses. Thus, our work opens the possibility that preventing negative tau modifications could enhance brain function through the improvement of mitochondrial health.