Regional contributions of D-serine to Alzheimer's disease pathology in male AppNL-G-F/NL-G-F mice.

Background: Neurodegenerative 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 methods: We 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. Results: Expression 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. Conclusion: These 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.

Complex Processes Underlying the Dynamic Changes of D-serine Levels in AD Brains.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular ß-amyloid (Aß) plaques and cognitive impairments. D-Serine, produced by the enzyme serine racemase (SR) in the brain, functions as an endogenous co-agonist at the glycine-binding site of N-methyl-D-aspartate receptor (NMDAR), has been implicated in the pathophysiological progression of AD. OBJECTIVES: Evidence regarding the understanding of the role and dynamic modulation of D-serine during AD progression remains controversial. This literature review aims to offer novel research directions for studying the functions and metabolisms of D-serine in AD brains. METHODS: We searched PubMed, using D-serine/SR and AD as keywords. Studies related to NMDAR dysfunction, neuronal excitotoxicity, D-serine dynamic changes and inflammatory response were included. RESULTS: This review primarily discusses: (i) Aß oligomers' role in NMDAR dysregulation, and the subsequent synaptic dysfunction and neuronal damage in AD, (ii) D-serine's role in NMDAR-elicited excitotoxicity, and (iii) the involvement of D-serine and SR in AD-related inflammatory pathological progression. CONCLUSION: We also presented supposed metabolism and dynamic changes of D-serine during AD progression and hypothesized that: (i) the possible modulation of D-serine levels or SR expression as an effective method of alleviating neurotoxicity during AD pathophysiological progression, and (ii) the dynamic changes of D-serine levels in AD brains possibly resulting from complex processes.

Blockade of D-serine signaling and adult hippocampal neurogenesis attenuates remote contextual fear memory following multiple memory retrievals in male mice.

The retrieval of fear memories induces two opposing processes, reconsolidation, and extinction. The memory reconsolidation is an active process that involves gene expression and updates an existing memory. It is hypothesized that blockade of reconsolidation by manipulating the neurobiological factors, which are mechanistically involved in the process, could weaken or disrupt the original fear memory. The N-methyl-D-aspartate (NMDA) receptor and hippocampal neurogenesis play crucial roles in hippocampus-dependent memory processes, including reconsolidation. Using contextual fear conditioning paradigm with multiple retrievals, we attempted to weaken the original contextual fear memory by repeatedly disrupting retrieval-induced reconsolidation via downregulation of NMDA receptor signaling and inhibition of neurogenesis. In the first experiment, prior to fear conditioning, NMDA receptor signaling was downregulated by the genetic reduction of its co-agonist, D-serine, and the neurogenesis was dampened by focal X-ray irradiation on the hippocampus. We found that simultaneous D-serine reduction and neurogenesis dampening resulted in a progressive decrease in freezing following each retrieval, leading to an attenuation of remote contextual fear memory on day 28. In the second experiment using the same behavioral protocols, after conditioning, pharmacological approaches were conducted to simultaneously block D-serine signaling and neurogenesis, resulting in a similar suppressive effect on the remote fear memory. The present findings provide insights for understanding the role of D-serine-mediated NMDA receptor signaling and neurogenesis in memory retrieval and the maintenance of remote fear memory, and improving the efficacy of exposure-based therapy for the treatment of post-traumatic stress disorder (PTSD).