Imagine the brain as a complex road system, with different regions representing different neighborhoods. In this study, scientists investigated the role of D-serine, a molecule that acts like a co-pilot, in Alzheimer’s disease (AD). Just like a helpful co-pilot can guide you through rough roads, D-serine plays a role in excitotoxicity, a process linked to nerve cell damage in AD. By studying genetically modified mice that mimic AD symptoms, the researchers found that decreased levels of D-serine were associated with reduced neuronal density and increased astroglial reactions. They also discovered that supplementing the mice’s water with D-serine worsened neurodegeneration, while deleting the gene responsible for producing D-serine had a partially protective effect. Excitingly, by manipulating the levels of D-serine in the brain, the researchers were able to observe improvements in neuronal health. These findings provide valuable insights into the fundamental mechanisms underlying AD pathology and hint at new therapeutic strategies for managing neurodegeneration. To dive deeper into this research, check out the full article!

BackgroundNeurodegenerative processes in Alzheimer’s disease (AD) are associated with excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR). D-Serine is an endogenous co-agonist necessary for NMDAR-mediated excitotoxicity. In the mammalian brain, it is produced by serine racemase (SRR) from L-serine, suggesting that dysregulation of L-serine, D-serine, or SRR may contribute to AD pathogenesis.Objective and methodsWe examined the contributions of D-serine to AD pathology in the AppNL–G–F/NL–G–F gene knock-in (APPKI) mouse model of AD. We first examined brain SRR expression levels and neuropathology in APPKI mice and then assessed the effects of long-term D-serine supplementation in drinking water on neurodegeneration. To further confirm the involvement of endogenous D-serine in AD progression, we generated Srr gene-deleted APPKI (APPKI-SRRKO) mice. Finally, to examine the levels of brain amino acids, we conducted liquid chromatography–tandem mass spectrometry.ResultsExpression of SRR was markedly reduced in the retrosplenial cortex (RSC) of APPKI mice at 12 months of age compared with age-matched wild-type mice. Neuronal density was decreased in the hippocampal CA1 region but not altered significantly in the RSC. D-Serine supplementation exacerbated neuronal loss in the hippocampal CA1 of APPKI mice, while APPKI-SRRKO mice exhibited attenuated astrogliosis and reduced neuronal death in the hippocampal CA1 compared with APPKI mice. Furthermore, APPKI mice demonstrated marked abnormalities in the cortical amino acid levels that were partially reversed in APPKI-SRRKO mice.ConclusionThese findings suggest that D-serine participates in the regional neurodegenerative process in the hippocampal CA1 during the amyloid pathology of AD and that reducing brain D-serine can partially attenuate neuronal loss and reactive astrogliosis. Therefore, regulating SRR could be an effective strategy to mitigate NMDAR-dependent neurodegeneration during AD progression.

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