Neuroprotective effects of low fat-protein diet in the P301L mouse model of tauopathy

- Female P301L-tg are more severely affected by tauopathy than male P301L-tg mice.
- LFPD improves lifespan, cognitive and locomotor activity in P301L-tg mice.
- LFPD ameliorates cognition and locomotor activity more efficiently in females than male.
- LFPD induces a decrease of P-Tau agglomerates in female but not in male.

Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain. Although numerous studies in mouse models of Alzheimer disease (AD) have shown a correlation among diet, beta-amyloid and AD onset, little is known about the impact of diet on Tau. We investigated whether a low fat-protein diet (LFPD) may improve lifespan, cognitive and locomotor activity in P301L-tg mouse model of tauopathy. Our data indicate that LFPD has a beneficial effect on these parameters. Tg mice fed with standard diet shown a decrease in body weight, food intake and survival rate if compared to wild type animals. In contrast, LFPD counteracted weight loss, increased mortality and ameliorated cognitive and locomotor performances in tg mice. LFPD also reduced the abnormal accumulation of agglomerates of P-Tau (pathological features of tauopathies) and the expression of apoptotic markers (i.e., TUNEL immunopositive neurons) in the prefrontal cerebral cortex and hippocampus of P301L-tg mice. Interestingly, some of these effects are sex-dependent. For instance, tg females, but not males, fed with LFPD had a significant increase of body weight and a reduction of P-Tau agglomerates compared to tg fed with standard diet. These changes correlated with a more pronounced improvement of cognition and locomotor activity in females than in male tg fed with LFPD. Altogether, these results suggest a sex dependent neuroprotective effect of LFPD in P301L-tg mice, suggesting that lifestyle intervention strategies may be clinically relevant for delaying the onset of cognitive impairment and dementia, especially in females.