Protein Deficiency-Induced Behavioral Abnormalities and Neurotransmitter Loss in Aged Mice Are Ameliorated by Essential Amino Acids

Abstract

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 Seven Essential Amino Acids Improves Cognitive Function and Psychological and Social Function in Middle-Aged and Older Adults: A Double-Blind, Randomized, Placebo-Controlled Trial

“…It is not possible to elucidate the mechanism based solely on the results of this study, which aimed to investigate the intervention effect of essential amino acid intake. Our initial hypothesis regarding this composition, Amino LP7 ( 8 ), was based on the amino acid influx rate to the brain, which would reflect the requirement for each amino acid to maintain brain homeostasis against neurodegenerative processes; we composed a mixture of seven essential amino acids rich in leucine, phenylalanine, and lysine to directly match the ratios associated with the brain influx rate. It is possible that Amino LP7 acts via multiple mechanisms, including neurotransmitter compensation ( 8 ) and competitive inhibition of neurotoxic substance influx into the brain.…”

“…Our initial hypothesis regarding this composition, Amino LP7 ( 8 ), was based on the amino acid influx rate to the brain, which would reflect the requirement for each amino acid to maintain brain homeostasis against neurodegenerative processes; we composed a mixture of seven essential amino acids rich in leucine, phenylalanine, and lysine to directly match the ratios associated with the brain influx rate. It is possible that Amino LP7 acts via multiple mechanisms, including neurotransmitter compensation ( 8 ) and competitive inhibition of neurotoxic substance influx into the brain. As the constituents of Amino LP7 have high rates of influx into the brain via specific transporters (e.g., LAT-1), it is plausible that Amino LP7 not only delivers the neurotransmitter substrate into the brain but also competitively inhibits the blood-to-brain transfer of toxic amino acid metabolites, such as kynurenine, that share the same transporters ( 38 , 39 ).…”

“…A granular powder that contained seven essential amino acids, namely, 0.47 g of leucine, 0.42 g of phenylalanine, 0.33 g of lysine hydrochloride, 0.13 g of isoleucine, 0.08 g of histidine hydrochloride, 0.06 g of valine, and 0.01 g of tryptophan, was put in a sachet; this ratio (Amino LP7) was suggested to be effective in a previous animal study ( 8 ). Based on the previous study conducted on mice, the applicable daily intake of Amino LP7 for humans was calculated to be between 3 and 6 g. Based on this calculation, the first group was asked to take 1.5 g of Amino LP7 twice a day, for a total of 3 g of Amino LP7 per day (3 g intervention group, 3gIG).…”

“…The mechanism underlying the relationship between amino acid intake and neurocognitive function has been investigated in an intervention study in mice. In mice given a low-protein diet (LPD) for 2 months, impairment of learning and memory in cognitive function and agitation and disinhibition in behavior was observed ( 8 ). In relation to these abnormalities, there were deficiencies in neurotransmitters, such as gamma-aminobutyric acid, glutamate, glycine, dopamine, norepinephrine, serotonin, and aspartate, in the brains of LPD-fed mice.…”

Diet modulates components of animal personality in house sparrows: insights into a possible hormone-mediated mechanism

“…Studies that experimentally increased brain noradrenaline noted improved attention in rats (Sirviö et al 1993) and maze solving performance in mice (Avraham et al 1996). Moreover, study on aged mice showed that oral administration of seven essential amino acids (precursors of neurotransmitters) to low-protein diet mice reversed behaviour abnormalities related to learning and memory impairment (Sato et al 2020).…”