Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer's Disease.

Alteration of brain aerobic glycolysis is often observed early in the course of Alzheimer's disease (AD). Whether and how such metabolic dysregulation contributes to both synaptic plasticity and behavioral deficits in AD is not known. Here, we show that the astrocytic l-serine biosynthesis pathway, which branches from glycolysis, is impaired in young AD mice and in AD patients. l-serine is the precursor of d-serine, a co-agonist of synaptic NMDA receptors (NMDARs) required for synaptic plasticity. Accordingly, AD mice display a lower occupancy of the NMDAR co-agonist site as well as synaptic and behavioral deficits. Similar deficits are observed following inactivation of the l-serine synthetic pathway in hippocampal astrocytes, supporting the key role of astrocytic l-serine. Supplementation with l-serine in the diet prevents both synaptic and behavioral deficits in AD mice. Our findings reveal that astrocytic glycolysis controls cognitive functions and suggest oral l-serine as a ready-to-use therapy for AD.

Molecular characterization and expression analysis of a phosphoserine aminotransferase involving l-serine synthesis from silkworm, Bombyx mori.

In this study, we identified and characterized a phosphoserine aminotransferase (bmPSAT) from Bombyx mori (B. mori) that is responsible for l-serine biosynthesis. A complementary DNA that encodes bmPSAT was cloned by reverse transcriptase polymerase reaction and sequenced. The presumed amino acid sequence revealed 47-87% identity with known PSATs from insects, humans, plants, and bacteria. Through phylogenetic analysis, we found that bmPSAT is evolutionary related to insect PSATs. Recombinant bmPSAT was produced in Escherichia coli by using a cold-shock promotor and purified to homogeneity. This enzyme utilizes phosphohydroxypyruvate and glutamate for transamination. bmPSAT messenger RNA (mRNA) was expressed at higher levels in several tissues of standard strain silkworm including the silk gland, whereas a sericin-deficient silkworm strain exhibited a diminished expression of bmPSAT mRNA in the silk gland. These findings indicate that bmPSAT may play an important role in synthesizing and supplying l-serine in the larva of B. mori.

Comparison of the Effect of Soy and Casein-Derived Peptide Administration on Tyrosine and Catecholamine Metabolism in the Mouse Brain.

The effect of soy and casein peptide intake on the metabolism of amino acids and monoamine neurotransmitters in the serum and brain were examined in C57BL/6 mice. Acute oral administration of soy peptide (0.026 g/30 g body weight) caused a notable increase in tyrosine, a catecholamine precursor, in the serum and cerebral cortex, whereas casein peptide administration at the same dose led to an increase in tyrosine in the serum, but not in the cerebral cortex. In addition to tyrosine, soy peptide administration also led to an effective augmentation of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), a principal metabolite of noradrenaline, and significant facilitation of noradrenergic turnover in the cerebral cortex, brainstem, and hippocampus compared to the vehicle control. Casein peptide administration also led to an increase in MHPG only in the cerebral cortex, and caused facilitation of noradrenergic turnover in the cerebral cortex and brainstem. These in vivo observations suggest that both soy and casein peptide intake at this concentration can lead to an increased availability of tyrosine and stimulation of noradrenergic turnover in the brain.