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

Xiance Ni; Ran Inoue; Yi Wu; Tomoyuki Yoshida; Keisuke Yaku; Takashi Nakagawa; Takashi Saito; Takaomi C Saido; Keizo Takao; Hisashi Mori

doi:10.3389/fnagi.2023.1211067

Regional contributions of D-serine to Alzheimer's disease pathology in male App^{NL-G-F/NL-G-F} mice

Front Aging Neurosci. 2023 Jun 29:15:1211067. doi: 10.3389/fnagi.2023.1211067. eCollection 2023.

Authors

Xiance Ni^#^{1

2}, Ran Inoue^#^{1

3}, Yi Wu^{1

2}, Tomoyuki Yoshida^{1

3}, Keisuke Yaku⁴, Takashi Nakagawa^{4

5}, Takashi Saito^{6

7}, Takaomi C Saido⁶, Keizo Takao^{3

5

8}, Hisashi Mori^{1

3

5}

Affiliations

¹ Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama, Toyama, Japan.
² Graduate School of Innovative Life Science, University of Toyama, Toyama, Japan.
³ Research Center for Idling Brain Science, University of Toyama, Toyama, Japan.
⁴ Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama, Japan.
⁵ Research Center for Pre-Disease Science, University of Toyama, Toyama, Japan.
⁶ Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan.
⁷ Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan.
⁸ Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama, Japan.

^# Contributed equally.

Abstract

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 App^{NL-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.

Keywords: Alzheimer’s disease; D-serine; amino acid homeostasis; excitotoxicity; neurodegeneration; serine racemase.

Grants and funding

This work was supported by the Grant of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (KAKENAI grant Nos. 18K06888 and 23K06354) and TAKEDA Science Foundation. XN is supported by Japan Educational Exchanges and Services (JEES) and Rotary Yoneyama Memorial Scholarships.