AbstractBackgroundNutritional epidemiology has implicated dietary protein intake in senile dementias. However, mechanistic links of protein and amino acids to age‐related neurodegenerative conditions remain unclear. Here, we tested the hypothesis that dietary intake of protein and amino acids could affect neuronal functions and survival in a mouse model of tauopathies, which develops tau pathologies leading to progressive brain atrophy with aging.MethodsNon‐transgenic (nTg) and tauopathy model (rTg4510) mice were fed a normal protein diet (NPD) or low protein diet (LPD) from 3 months of age, and brain volume and tau pathologies were measured at 6.5 months of age by MRI and PET, respectively. These imaging assays were also applied to NPD‐ and LPD‐fed mice treated with essential amino acids (EAAs), seven essential amino acids (EAAs), which are primarily composed of leucine, phenylalanine, and lysine with high fluxes into the brain and contain minimum levels of tryptophan, an origin of inflammation‐related kynurenine pathways. Moreover, we performed gene expression profiling of the cortical tissues collected from these mice.ResultsLPD profoundly accelerated the brain atrophy in rTg4510 mice relative to NPD. EAA supplementation to rTg4510 mice markedly suppressed cortical volume reductions in both LPD‐ and NPD‐fed rTg4510. LPD and EAA did not overtly alter PET‐detectable tau depositions uncorrected for atrophy‐induced partial volume effects, raising a possibility of decreased tau burdens in each of surviving neurons to some extent. Gene expression profiling demonstrated neuroinflammatory changes and neuronal dysfunctions in rTg4510 mice, which were worsened by LPD and attenuated by EAAs. Notably, kynurenine levels were elevated by LPD, and this alteration was reversed by EEAs, presumably by competition between EEAs and kynurenine on the entry into the brain.ConclusionOur findings highlight the critical roles of specific EEAs in the protection of neurons against tau‐induced toxicity and neuroinflammation.