Nutritional epidemiology shows that insufficient protein intake is related to senile dementia. The levels of protein intake in aged people are positively associated with memory function, and elderly people with high protein intake have a low risk of mild cognitive impairment. Although the beneficial roles of protein nutrition in maintaining brain function in aged people are well demonstrated, little is known about the mechanism by which dietary intake of protein affects memory and brain conditions. We fed aged mice a low protein diet (LPD) for 2 months, which caused behavioral abnormalities, and examined the nutritional effect of essential amino acid administration under LPD conditions. The passive avoidance test revealed that LPD mice demonstrated learning and memory impairment. Similarly, the LPD mice showed agitation and hyperactive behavior in the elevated plus maze test. Moreover, LPD mice exhibited decreased concentrations of gamma-aminobutyric acid (GABA), glutamate, glycine, dopamine, norepinephrine, serotonin and aspartate in the brain. Interestingly, oral administration of seven essential amino acids (EAAs; valine, leucine, isoleucine, lysine, phenylalanine, histidine, and tryptophan) to LPD mice, which can be a source of neurotransmitters, reversed those behavioral changes. The oral administration of EAAs restored the brain concentration of glutamate, which is involved in learning and memory ability and may be associated with the observed behavioral changes. Although the details of the link between decreased amino acid and neurotransmitter concentrations and behavioral abnormalities must be examined in future studies, these findings suggest the importance of dietary protein and essential amino acids for maintaining brain function.

Intake of specific seven essential amino acids affects the pathology of the brain.

BackgroundNutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants.MethodIn a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal (“MCI-stable,” N = 87) and converted to Alzheimer’s disease (AD) (“AD-convert,” N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted.ResultsPlasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group.ConclusionThe PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status.Clinical trial registration[https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965].

Background Nutritional 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. Methods Non‐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. Results LPD 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. Conclusion Our findings highlight the critical roles of specific EEAs in the protection of neurons against tau‐induced toxicity and neuroinflammation.

Background Primary prevention of cognitive decline is important while development of disease modifying drugs for early Alzheimer's Disease (AD) is progressing rapidly. As a screening tool for early detection of cognitive decline, blood‐based biomarkers prior to invasive testing such as cerebral spinal fluid examination and positron emission tomography scanning could be beneficial. In our small‐scale pilot study, plasma‐free amino acid (PFAA) profiles of AD patients and mild cognitive impairment (MCI) due to AD were shown to be significantly different from those of cognitively healthy elderly. In order to examine the clinical significance of PFAAs as a novel biomarker, we started an MCI cohort study that enrolls hundreds of MCI subjects to determine practical biomarkers for MCI screening among generally healthy subjects, and to distinguish stable MCI and AD‐converted MCI. The results of interim baseline analysis regarding MCI screening will be presented here. Method MCI subjects from 6 medical sites in Japan (MCI, n=117) and age‐gender‐matched community dwellers in 3 different cities in Japan (healthy control, n=117) were included in the current analysis. At baseline visit, plasma samples were collected under fasting condition. The concentrations of PFAAs and plasma amines were analyzed with LC/MS or LC/MS/MS and serum biochemistry tests were done. Observation of the clinical status of MCI subjects for 3 years after the blood collection is ongoing. Result Several PFAAs including essential amino acids of MCI subjects were significantly lower than those of healthy control. There were no significant differences in plasma amine concentrations between MCI and control group. In addition, several serum biochemistry parameters including serum albumin of MCI subjects were significantly lower. These differences were independent of age and gender. Conclusion Both PFAAs including essential amino acids and serum biochemistry including albumin were shown to be potential biomarkers for MCI screening. The validation of this results will be conducted in another subset in this MCI cohort study. For further investigation, we will conduct multivariable analysis and create the robust algorithm for MCI screening. Also, observation of the clinical status of MCI subjects will continue to distinguish stable MCI and AD‐converted MCI.