Abstract
Serine racemase (SR) dysregulation associates with brain aging and Alzheimer’s disease (AD), as both a deficiency and an excess of D-serine can impact synaptic neurotransmission and the integrity of synapses. Neuronal SR decreases with aging, while glial SR is upregulated in AD. However, the role of SR in microglia involved in AD remains elusive. Here, Srr knockdown/knockout in microglia enhanced whereas overexpression of SR inhibited phagocytosis. Lipopolysaccharide-treated Srr−/− microglia upregulated anti-inflammatory factors—an effect blocked by histone lactylation inhibition. Conditional microglial Srr knockout (5×FAD;Lyz2cre;Srrfl/fl) improved spatial memory and reduced amyloid plaques (male-specific) in 5×FAD mice, with elevated lactylation of histone H3 lysine 18 (H3K18la), pyruvate kinase M2, and arginase1 in plaque-associated microglia. Cerebral D-amino acid oxidase and microglial SR and H3K18la were more prominent in males. Collectively, microglia-specific Srr deletion reprograms microglia toward an anti-inflammatory phenotype and enhanced phagocytic capacity partialy mediated by histone lactylation, thereby mitigating AD neuropathology and improving cognitive function—where sex-specific modulation of D-serine contributes to these beneficial effects. Overall, this study delineates the functional roles of microglial SR in phagocytosis, inflammatory responses, and learning-memory behaviors in AD-related models, thereby implicating microglial SR as a potential therapeutic target for AD.
Data availability
All the figures in the main manuscript and supplemental information were also deposited in the figshare repository at https://doi.org/10.6084/m9.figshare.30252505. The numerical source data for the graphs were provided in Supplemental Data 1. The uncropped gels were provided as Supplementary Figs. in Supplementary information pdf. The newly generated plasmid was deposited in a community repository, WESTLAKE LABORATORIES, with the link, https://wekwikgene.wllsb.edu.cn and the barcode# 0002358, the name, Srr-IRES-GFP.
References
Mattson, M. P. Pathways towards and away from Alzheimer’s disease. Nature 430, 631–639 (2004).
Cherry, J. D., Olschowka, J. A. & O’Banion, M. K. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J. Neuroinflammation 11, 98 (2014).
Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).
Barger, S. W. & Basile, A. S. Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J. Neurochem. 76, 846–854 (2001).
Streit, W. J., Mrak, R. E. & Griffin, W. S. Microglia and neuroinflammation: a pathological perspective. J. Neuroinflammation 1, 14 (2004).
Murenu, E., Gerhardt, M. J., Biel, M. & Michalakis, S. More than meets the eye: the role of microglia in healthy and diseased retina. Front. Immunol. 13, 1006897 (2022).
Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).
Prinz, M., Jung, S. & Priller, J. Microglia biology: one century of evolving concepts. Cell 179, 292–311 (2019).
Sosna, J. et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease. Mol. Neurodegener. 13, 11 (2018).
Spangenberg, E. et al. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nat. Commun. 10, 3758 (2019).
Sheng, J. G., Griffin, W. S., Royston, M. C. & Mrak, R. E. Distribution of interleukin-1-immunoreactive microglia in cerebral cortical layers: implications for neuritic plaque formation in Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 24, 278–283 (1998).
Mrak, R. E. & Griffin, W. S. Interleukin-1 and the immunogenetics of Alzheimer disease. J. Neuropathol. Exp. Neurol. 59, 471–476 (2000).
Grubman, A. et al. Transcriptional signature in microglia associated with Abeta plaque phagocytosis. Nat. Commun. 12, 3015 (2021).
Michaud, J. P., Bellavance, M. A., Prefontaine, P. & Rivest, S. Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep. 5, 646–653 (2013).
Baik, S. H. et al. A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab. 30, 493–507.e496 (2019).
Pan, R. Y. et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metab. 34, 634–648.e636 (2022).
Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).
Barger, S. W., Goodwin, M. E., Porter, M. M. & Beggs, M. L. Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation. J. Neurochem. 101, 1205–1213 (2007).
Wu, S. Z. et al. Induction of serine racemase expression and D-serine release from microglia by amyloid beta-peptide. J. Neuroinflammation 1, 2 (2004).
Zhang, H. et al. Alterations of serine racemase expression determine proliferation and differentiation of neuroblastoma cells. FASEB J. 36, e22473 (2022).
Zhang, H. et al. Reduced serine racemase expression in aging rat cerebellum is associated with oxidative DNA stress and hypermethylation in the promoter. Brain Res. 1629, 221–230 (2015).
Zhang, H., Lu, J. & Wu, S. Sp4 controls constitutive expression of neuronal serine racemase and NF-E2-related factor-2 mediates its induction by valproic acid. Biochim. Biophys. Acta Gene Regul. Mech. 1863, 194597 (2020).
Madeira, C. et al. d-serine levels in Alzheimer’s disease: implications for novel biomarker development. Transl. Psychiatry 5, e561 (2015).
Wu, S. & Barger, S. W. Induction of serine racemase by inflammatory stimuli is dependent on AP-1. Ann. N. Y Acad. Sci. 1035, 133–146 (2004).
Balu, D. T. et al. Neurotoxic astrocytes express the D-serine synthesizing enzyme, serine racemase, in Alzheimer’s disease. Neurobiol. Dis. 130, 104511 (2019).
Turpin, F. R. et al. Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function. Neurobiol. Aging 32, 1495–1504 (2011).
Billard, J. M. et al. Early involvement of D-serine in β-amyloid-dependent pathophysiology. Cell. Mol. Life Sci. 82, 179 (2025).
Wu, S. Z., Jiang, S., Sims, T. J. & Barger, S. W. Schwann cells exhibit excitotoxicity consistent with release of NMDA receptor agonists. J. Neurosci. Res. 79, 638–643 (2005).
Mustafa, A. K. et al. Serine racemase deletion protects against cerebral ischemia and excitotoxicity. J. Neurosci. 30, 1413–1416 (2010).
Inoue, R., Hashimoto, K., Harai, T. & Mori, H. NMDA- and beta-amyloid1-42-induced neurotoxicity is attenuated in serine racemase knock-out mice. J. Neurosci. 28, 14486–14491 (2008).
Jiang, H. et al. Loss-of-function mutation of serine racemase attenuates retinal ganglion cell loss in diabetic mice. Exp. Eye Res. 175, 90–97 (2018).
Mothet, J. P. et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc. Natl. Acad. Sci. USA 97, 4926–4931 (2000).
Arizanovska, D. et al. Cognitive loss after brain trauma results from sex-specific activation of synaptic pruning processes. Brain https://doi.org/10.1093/brain/awaf293 (2025).
Tapanes, S. A. et al. Inhibition of glial D-serine release rescues synaptic damage after brain injury. Glia 70, 1133–1152 (2022).
Ni, X. et al. Regional contributions of D-serine to Alzheimer’s disease pathology in male App(NL-G-F/NL-G-F) mice. Front Aging Neurosci. 15, 1211067 (2023).
Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575 (2019).
Wang, N. et al. Histone lactylation boosts reparative gene activation post-myocardial infarction. Circ. Res. 131, 893–908 (2022).
Wang, S. et al. TREM2 drives microglia response to amyloid-beta via SYK-dependent and -independent pathways. Cell 185, 4153–4169.e4119 (2022).
Wong, J. M. et al. Postsynaptic serine racemase regulates NMDA receptor function. J. Neurosci. 40, 9564–9575 (2020).
Wu, M. et al. Intravenous injection of l-aspartic acid beta-hydroxamate attenuates choroidal neovascularization via anti-VEGF and anti-inflammation. Exp. Eye Res. 182, 93–100 (2019).
Wang, S. et al. Effects of topic delivery of an inhibitor of serine racemase on laser-induced choroidal vasculopathy. Transl. Vis. Sci. Technol. 13, 24 (2024).
Chaneton, B. et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458–462 (2012).
Clark, L. C. Jr., Kochakian, C. D. & Fox, R. P. The effect of castration and testosterone propionate on D-amino acid oxidase activity in the mouse. Science 98, 89 (1943).
Konno, R. & Yasumura, Y. Mouse mutant deficient in D-amino acid oxidase activity. Genetics 103, 277–285 (1983).
Endahl, B. R. & Kochakian, C. D. Role of castration and androgens in D-amino acid oxidase activity of tissues. Am. J. Physiol. 185, 250–256 (1956).
Torres Jimenez, N. et al. Electroretinographic abnormalities and sex differences detected with mesopic adaptation in a mouse model of schizophrenia: A and B wave analysis. Invest Ophthalmol. Vis. Sci. 61, 16 (2020).
Villa, A. et al. Sex-specific features of microglia from adult mice. Cell Rep. 23, 3501–3511 (2018).
Ferretti, M. T. et al. Sex differences in Alzheimer disease—the gateway to precision medicine. Nat. Rev. Neurol. 14, 457–469 (2018).
Yanguas-Casas, N. et al. Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid. Glia 66, 522–537 (2018).
Xiong, J. et al. FSH blockade improves cognition in mice with Alzheimer’s disease. Nature 603, 470–476 (2022).
Xiong, J. et al. FSH and ApoE4 contribute to Alzheimer’s disease-like pathogenesis via C/EBPbeta/delta-secretase in female mice. Nat. Commun. 14, 6577 (2023).
Nelson, P. T. et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71, 362–381 (2012).
Moscoso, A. et al. Frequency and clinical outcomes associated with tau positron emission tomography positivity. JAMA. 334, 229–242 (2025).
Malpas, C. B. et al. Tau and amyloid-beta cerebrospinal fluid biomarkers have differential relationships with cognition in mild cognitive impairment. J. Alzheimers Dis. 47, 965–975 (2015).
Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017).
Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581.e569 (2017).
Millet, A., Ledo, J. H. & Tavazoie, S. F. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains. Immunity 57, 153–170.e156 (2024).
Zhou, J. et al. Deletion of serine racemase reverses neuronal insulin signaling inhibition by amyloid-beta oligomers. J. Neurochem 163, 8–25 (2022).
Wang, Y., Lian, M., Zhou, J. & Wu, S. Brain Dicer1 is down-regulated in a mouse model of Alzheimer’s disease via Abeta42-induced repression of nuclear factor erythroid 2-related factor 2. Mol. Neurobiol. 57, 4417–4437 (2020).
Wang, Y. et al. Dicer1 promotes Abeta clearance via blocking B2 RNA-mediated repression of apolipoprotein E. Biochim. Biophys. Acta Mol. Basis Dis. 1867, 166038 (2021).
Lian, H., Roy, E. & Zheng, H. Microglial phagocytosis assay. Bio Protoc. 6, e1988 (2016).
Acknowledgements
This study was supported by National Natural Science Foundation of China for Young Scholars (82301614), and an intramural grant, Integrated Project of State Key Laboratory of School of Optometry and Ophthalmology, Wenzhou Medical University (J02-20190204).
Author information
Authors and Affiliations
Contributions
J. Zhou: Investigation, visualization, and funding acquisition; Y.H. Yang: Investigation and visualization; S.Y. Liu: Investigation and visualization; J. Chen: Investigation; H.J. Liao: Investigation; W.J. Liang: Investigation; Z.W. Zhang: Investigation; Y. Wang: Investigation; Y.M. Liu: Investigation; H. Zhang: Investigation; H.Y. Jiang: Investigation; W.C. Lin: Methodology; J. Qu: Supervision and methodology; S.W. Barger: Revision and discussion; S.Z. Wu: Conceptualization, supervision, and writing.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editors: Ibrahim Javed and Joao Valente. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Zhou, J., Yang, Y., Liu, S. et al. Microglial serine racemase knockout alleviates Alzheimer-like neuropathology and behavioral deficit via lactylation-mediated anti-inflammation. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09772-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s42003-026-09772-y
