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

Frontiers in Aging Neuroscience

Neuroscience

Xiance Ni¹  Yi Wu¹  Ran Inoue²  Tomoyuki Yoshida²  Hisashi Mori³  Keisuke Yaku⁴  Takashi Nakagawa⁵  Takaomi C. Saido⁶  Takashi Saito⁷  Keizo Takao⁸ 

[1] Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama, Toyama, Japan;Graduate School of Innovative Life Science, University of Toyama, Toyama, Japan;Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama, Toyama, Japan;Research Center for Idling Brain Science, University of Toyama, Toyama, Japan;Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama, Toyama, Japan;Research Center for Idling Brain Science, University of Toyama, Toyama, Japan;Research Center for Pre-Disease Science, University of Toyama, Toyama, Japan;Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama, Japan;Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama, Japan;Research Center for Pre-Disease Science, University of Toyama, Toyama, Japan;Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan;Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan;Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan;Research Center for Idling Brain Science, University of Toyama, Toyama, Japan;Research Center for Pre-Disease Science, University of Toyama, Toyama, Japan;Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama, Japan;

关键词: Alzheimer’s disease;    -serine;    serine racemase;    excitotoxicity;    neurodegeneration;    amino acid homeostasis;   

DOI  :  10.3389/fnagi.2023.1211067

 received in 2023-04-24, accepted in 2023-06-05,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Ni, Inoue, Wu, Yoshida, Yaku, Nakagawa, Saito, Saido, Takao and Mori.