CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
Open accessAbstract
Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.
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Restoration of microglial phagocytosis improves cognitive function in aged mice and promotes a homeostatic microglial transcriptional signature.
“restoration of microglial phagocytosis improved cognitive function in aged mice and promoted a homeostatic microglial transcriptional signature78.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [78]
The 82 genes were strongly enriched for up-regulated genes with immune-modulatory functions, including MHC I-mediated antigen presentation, interferon-response, cell adhesion and complement cascade, as well as regulators of mouse microglia activity including Cd22, Trem2 and Tyrobp.
“These were strongly enriched for up-regulated genes with immune-modulatory functions (Table S5), including MHC I-mediated antigen presentation, interferon-response, cell adhesion and complement cascade, as well as regulators of mouse microglia activity (Figure 2C) including Cd22 (Pluvinage et al., 2019), Trem2 and Tyrobp (Yeh et al., 2017).”
From Atlas of the aging mouse brain reveals white matter as vulnerable foci (2023) · cites this paper as Pluvinage et al., 2019
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“The functional decline of aged microglia may result from the upregulation of CD22; thus, the inhibition of CD22 can enhance the clearance of debris and fibrils, including Aβ oligomers, in vivo, and this process may be potentially beneficial for the treatment of AD.(241) Considerable evidence suggests that the use of a…”
BackgroundMicroglia and Central Nervous System–Associated Macrophages—From Origin to Disease Modulation
Prinz, M., Masuda, T., Wheeler, M. A., & Quintana, F. J. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-093019-110159 · Cited by 584 · see citing works
The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans
Smith, B. A. H., & Bertozzi, C. R. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-00093-1 · Cited by 504 · see citing works
Self-citationPhysiological blood–brain transport is impaired with age by a shift in transcytosis
Yang, A. C., Stevens, M. Y., Chen, M. B., Lee, D. P., Stähli, D., Gate, D., Contrepois, K., Chen, W., Iram, T., Zhang, L., et al. (2020) · Nature · doi:10.1038/s41586-020-2453-z · Cited by 477 · see citing works
Self-citationParkinson disease and the immune system - Associations, mechanisms and therapeutics
Tan, E.-K., Chao, Y.-X., West, A., Chan, L.-L., Poewe, W., & Jankovic, J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0344-4 · Cited by 457 · see citing works
Siglecs as Immune Cell Checkpoints in Disease
Duan, S., & Paulson, J. C. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-102419-035900 · Cited by 452 · see citing works
Microglia-organized scar-free spinal cord repair in neonatal mice
Li, Y., He, X., Kawaguchi, R., Zhang, Y., Wang, Q., Monavarfeshani, A., Yang, Z., Chen, B., Shi, Z., Meng, H., et al. (2020) · Nature · doi:10.1038/s41586-020-2795-6 · Cited by 434 · see citing works
Transforming the understanding of brain immunity
Castellani, G., Croese, T., Peralta Ramos, J. M., & Schwartz, M. (2023) · Science · doi:10.1126/science.abo7649 · Cited by 386 · see citing works
“Inhibition of the B cell receptor CD22 protein, a negative regulator of phagocytosis that is up-regulated in aged microglia, was found to restore the phagocytic capacity of microglia in vivo and to improve cognition in agedmice (97).”
BackgroundMicroglia Actively remodel adult hippocampal neurogenesis through the phagocytosis secretome
Diaz-Aparicio, I., Paris, I., Sierra-Torre, V., Plaza-Zabala, A., Rodríguez-Iglesias, N., Márquez-Ropero, M., Beccari, S., Huguet, P., Abiega, O., Alberdi, E., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.0993-19.2019 · Cited by 333 · see citing works
SYK coordinates neuroprotective microglial responses in neurodegenerative disease
Ennerfelt, H., Frost, E. L., Shapiro, D. A., Holliday, C., Zengeler, K. E., Voithofer, G., Bolte, A. C., Lammert, C. R., Kulas, J. A., Ulland, T. K., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.030 · Cited by 329 · see citing works
Xiao, X., Huang, S., Chen, S., Wang, Y., Sun, Q., Xu, X., & Li, Y. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02148-6 · Cited by 326 · see citing works
“CD22 is also expressed in microglia in the human brain [107], whereas there is no evidence indicating that the severity of ICANS is increased in CD22 CAR T-cell therapy.”
BackgroundCAR T cells: Continuation in a revolution of immunotherapy
Singh, A. K., & McGuirk, J. P. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30823-x · Cited by 303 · see citing works
BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease
Moussa‐Pacha, N. M., Abdin, S. M., Omar, H. A., Alniss, H. Y., & Al‐Tel, T. H. (2019) · Medicinal Research Reviews · doi:10.1002/med.21622 · Cited by 308 · see citing works
Microglial phagocytosis of neurons in neurodegeneration, and its regulation
Butler, C. A., Popescu, A. S., Kitchener, E. J. A., Allendorf, D. H., Puigdellívol, M., & Brown, G. C. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15327 · Cited by 293 · see citing works
“CD22 blockade restores homeostatic microglial phagocytosis in ageing brains.”
BackgroundInfluentialEmerging phagocytosis checkpoints in cancer immunotherapy
Liu, Y., Wang, Y., Yang, Y., Weng, L., Wu, Q., Zhang, J., Zhao, P., Fang, L., Shi, Y., & Wang, P. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01365-z · Cited by 287 · see citing works
“Longterm CD22 blockade changes the transcriptional profile of microglia, including genes associated with microglial homeostasis, and improves cognitive function in aged mice.(132) CD22-mediated phagocytosis in TAMs and in cancer immunotherapy requires further study.”
BackgroundInfluentialStanczak, M. A., Mantuano, N. R., Kirchhammer, N., Sanin, D. E., Jacob, F., Coelho, R., Everest‐Dass, A., Wang, J., Trefny, M. P., Monaco, G., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abj1270 · Cited by 246 · see citing works
“Similarly, Siglec-2 (CD22) has been shown to mediate sialic acid–induced inhibition of microglial phagocytosis (30).”
Self-citationAging and Rejuvenation of Neural Stem Cells and Their Niches
Navarro Negredo, P., Yeo, R. W., & Brunet, A. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.07.002 · Cited by 246 · see citing works
Cien Años de Microglía: Milestones in a Century of Microglial Research
Sierra, A., Paolicelli, R. C., & Kettenmann, H. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.09.004 · Cited by 229 · see citing works
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“Considering that the brain is a primary and sensitive site of human disease, much research has focused on applying CRISPR-Cas9–based gene therapy to brain-related diseases (8, 9).”
BackgroundTargeting immune dysfunction in aging
Borgoni, S., Kudryashova, K. S., Burka, K., & de Magalhães, J. P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101410 · Cited by 227 · see citing works
“CD22 antibody blockade successfully reversed the transcriptional signature of aging brains in mice and improved cognitive functions (Pluvinage et al., 2019).”
Intersection of pathological tau and microglia at the synapse
Vogels, T., Murgoci, A.-N., & Hromádka, T. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0754-y · Cited by 197 · see citing works
Atlas of the aging mouse brain reveals white matter as vulnerable foci
Hahn, O., Foltz, A. G., Atkins, M., Kedir, B., Moran-Losada, P., Guldner, I. H., Munson, C., Kern, F., Pálovics, R., Lu, N., et al. (2023) · Cell · doi:10.1016/j.cell.2023.07.027 · Cited by 213 · see citing works
Self-citationPhagocytic microglia and macrophages in brain injury and repair
Yu, F., Wang, Y., Stetler, R. A., Leak, R. K., Hu, X., & Chen, J. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13899 · Cited by 209 · see citing works
Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17
Iram, T., Kern, F., Kaur, A., Myneni, S., Morningstar, A. R., Shin, H., García, M. Á., Yerra, L. P., Pálovics, R., Yang, A. C., et al. (2022) · Nature · doi:10.1038/s41586-022-04722-0 · Cited by 198 · see citing works
“In the Fgf17 blocking antibody experiments, the forced alternation Y-maze and contextual fear conditioning was performed as previously described 57 .”
MethodSelf-citationMicroglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer’s disease
Hu, J., Chen, Q., Zhu, H., Hou, L., Liu, W., Yang, Q., Shen, H., Chai, G., Zhang, B., Chen, S., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.021 · Cited by 196 · see citing works
Bido, S., Muggeo, S., Massimino, L., Marzi, M. J., Giannelli, S. G., Melacini, E., Nannoni, M., Gambarè, D., Bellini, E., Ordazzo, G., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26519-x · Cited by 190 · see citing works
Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration
Pluvinage, J. V., & Wyss-Coray, T. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0255-9 · Cited by 191 · see citing works
Self-citationAstrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions
Traiffort, É., Kassoussi, A., Zahaf, A., & Laouarem, Y. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00079 · Cited by 189 · see citing works
Microglia as Dynamic Cellular Mediators of Brain Function
Wright-Jin, E. C., & Gutmann, D. H. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.08.013 · Cited by 186 · see citing works
Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction
Konishi, H., Okamoto, T., Hara, Y., Komine, O., Tamada, H., Maeda, M., Osako, F., Kobayashi, M., Nishiyama, A., Kataoka, Y., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020104464 · Cited by 179 · see citing works
“However, impairment of microglial phagocytosis can occur in certain conditions, such as aging and injury (Abiega et al , 2016; Pluvinage et al , 2019).”
CNS remyelination and inflammation: From basic mechanisms to therapeutic opportunities
Franklin, R. J. M., & Simons, M. (2022) · Neuron · doi:10.1016/j.neuron.2022.09.023 · Cited by 184 · see citing works
Directed evolution of adeno-associated virus for efficient gene delivery to microglia
Lin, R., Zhou, Y., Yan, T., Wang, R., Li, H., Wu, Z., Zhang, X., Zhou, X., Zhao, F., Zhang, L., et al. (2022) · Nature Methods · doi:10.1038/s41592-022-01547-7 · Cited by 171 · see citing works
“Microglial dysfunction is a key factor in CNS ageing 12 and in the progression of CNS diseases including neurodegenerative disorders 13–15 and brain cancers 16–18 .”
Transcriptomic profiling of microglia and astrocytes throughout aging
Pan, J., Ma, N., Yu, B., Zhang, W., & Wan, J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01774-9 · Cited by 188 · see citing works
Microglia regulation of central nervous system myelin health and regeneration
Kent, S. A., & Miron, V. E. (2024) · Nature Reviews Immunology · doi:10.1038/s41577-023-00907-4 · Cited by 183 · see citing works
“138).”
Function of Macrophages in Disease: Current Understanding on Molecular Mechanisms
Zhang, C., Yang, M. J., & Ericsson, A. C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.620510 · Cited by 162 · see citing works
“Moreover, other Siglecs including Siglec-2 (52), Siglec-3 (53), Siglec-4 (54), Siglec-5 (55, 56), Siglec-6 (57), Siglec-8 (59), Siglec-10 (61), Siglec-11 (62), Siglec-12 (63), Siglec15 (64) also play important roles in diseases as listed in Table 1.”
Blood-to-brain communication in aging and rejuvenation
Bieri, G., Schroer, A. B., & Villeda, S. A. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01238-8 · Cited by 156 · see citing works
Sialylation and Galectin-3 in Microglia-Mediated Neuroinflammation and Neurodegeneration
Puigdellívol, M., Allendorf, D. H., & Brown, G. C. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00162 · Cited by 145 · see citing works
Pharmacological Targeting of Microglial Activation: New Therapeutic Approach
Liu, C.-Y., Wang, X., Liu, C., & Zhang, H.-L. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00514 · Cited by 133 · see citing works
An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains
Millet, A., Ledo, J. H., & Tavazoie, S. F. (2024) · Immunity · doi:10.1016/j.immuni.2023.12.001 · Cited by 132 · see citing works
Emerging role of senescent microglia in brain aging-related neurodegenerative diseases
Rim, C., You, M., Nahm, M., & Kwon, M. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00402-3 · Cited by 147 · see citing works
“Restoration of phagocytosis in senescent microglia has been achieved by various means, including inhibition of the CD22 receptor, which is known for its interaction with low-density lipoprotein [151].”
BackgroundThe Role of Microglial Phagocytosis in Ischemic Stroke
Jia, J., Yang, L., Chen, Y., Zheng, L., Chen, Y., Xu, Y., & Zhang, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.790201 · Cited by 136 · see citing works
“For instance, CD22 blocks microglia-mediated engulfment of myelin debris in the aged brain, while CD22 blockade restores microglial homeostasis and cognitive impairment in aged mice (95).”
BackgroundWhite matter aging and its impact on brain function
Groh, J., & Simons, M. (2025) · Neuron · doi:10.1016/j.neuron.2024.10.019 · Cited by 124 · see citing works
Antignano, I., Liu, Y., Offermann, N., & Capasso, M. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04775-y · Cited by 117 · see citing works
“One of the responsible factors is CD22, a negative regulator of microglia phagocytosis [34, 35], whose expression in microglia in the CNS increases with age.”
BackgroundMicroglia in Alzheimer’s Disease: A Target for Therapeutic Intervention
Zhang, G., Wang, Z., Hu, H., Zhao, M., & Sun, L. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.749587 · Cited by 132 · see citing works
Zhou, T. G., Li, Y., Li, X., Zeng, F., Rao, Y., He, Y., Wang, Y., Liu, M., Li, D., Xu, Z., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33932-3 · Cited by 122 · see citing works
Microglia in Alzheimer’s Disease in the Context of Tau Pathology
Perea, J. R., Bolós, M., & Ávila, J. (2020) · Biomolecules · doi:10.3390/biom10101439 · Cited by 127 · see citing works
“Nevertheless, blockade of CD22 restores phagocytosis, and animals showed cognitive improvement [283].”
BackgroundReactive microglia enhance the transmission of exosomal α-synuclein via toll-like receptor 2
Xia, Y., Zhang, G., Kou, L., Yin, S., Han, C., Hu, J., Wan, F., Sun, Y., Wu, J., Li, Y., et al. (2021) · Brain · doi:10.1093/brain/awab122 · Cited by 123 · see citing works
The role of innate immunity in Alzheimer's disease
Ennerfelt, H. E., & Lukens, J. R. (2020) · Immunological Reviews · doi:10.1111/imr.12896 · Cited by 121 · see citing works
Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer’s disease pathology
Cheng, J., Dong, Y., Ma, J., Pan, R., Liao, Y., Kong, X., Li, X., Li, S., Chen, P.-F., Wang, L., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe3600 · Cited by 119 · see citing works
Poudel, P., & Park, S. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14040835 · Cited by 124 · see citing works
“CD-22 suppression facilitates the removal of Aβ fibrils from the brain, which could be a viable strategy to reduce the progression of neuroinflammation and AD [49].”
BackgroundMicroglial Corpse Clearance: Lessons From Macrophages
Márquez-Ropero, M., Benito, E., Plaza‐Zabala, A., & Sierra, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00506 · Cited by 112 · see citing works
“Phagocytosis therefore has a strong potential for impinging on the course of neurodegenerative diseases, as has been evidenced by blocking of the phagocytosis inhibitor CD22 in aging mouse brains to restore a microglial homeostatic profile and improve cognitive function (74).”
BackgroundInfluentialMicroglial efferocytosis: Diving into the Alzheimer’s disease gene pool
Romero-Molina, C., Garretti, F., Andrews, S. J., Marcora, E., & Goate, A. M. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.015 · Cited by 111 · see citing works
Putting the brakes on phagocytosis: “don't-eat-me” signaling in physiology and disease
Kelley, S. M., & Ravichandran, K. S. (2021) · EMBO Reports · doi:10.15252/embr.202152564 · Cited by 110 · see citing works
“CD22 was shown to inhibit microglial phagocytosis, presumably via activation of SHP-1, and loss of CD22 enhanced the clearance of several neurodegenerative factors, including myelin debris, A b oligomers, and a -synuclein fibrils in vitro and in vivo (Pluvinage et al, 2019).”
Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis
Schloesser, D., Lindenthal, L., Sauer, J., Chung, K., Chavakis, T., Griesser, E., Baskaran, P., Maier-Habelsberger, U., Fundel‐Clemens, K., Schlotthauer, I., et al. (2022) · The Journal of Cell Biology · doi:10.1083/jcb.202207097 · Cited by 113 · see citing works
“Anti-CD22 (ab218340) and anti-CD24 (ab179821) were obtained from Abcam.”
InfluentialTargeting microglia in brain disorders
Priller, J., & Prinz, M. (2019) · Science · doi:10.1126/science.aau9100 · Cited by 110 · see citing works
The aging mouse brain: cognition, connectivity and calcium
Radulescu, C. I., Cerar, V., Haslehurst, P., Kopanitsa, M. V., & Barnes, S. J. (2021) · Cell Calcium · doi:10.1016/j.ceca.2021.102358 · Cited by 105 · see citing works
Cellular senescence, DNA damage, and neuroinflammation in the aging brain
Zhang, W., Sun, H., Wang, X., Dumont, A. S., & Liu, Q. (2024) · Trends in Neurosciences · doi:10.1016/j.tins.2024.04.003 · Cited by 113 · see citing works
Li, J., Wei, Y., Zhou, J., Zou, H., Ma, L., Liu, C., Xiao, Z., Liu, X., Tan, X., Yu, T., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02489-9 · Cited by 106 · see citing works
“It has been confirmed that the NE receptors exist on both astrocytes and microglia derived from the brain [11, 12], and the SDH [13].”
BackgroundThe roles of microglia and astrocytes in myelin phagocytosis in the central nervous system
Xu, T., Liu, C., Deng, S., Gan, L., Zhang, Z., Yang, G., Tian, H., & Tang, Y. (2022) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x221137762 · Cited by 106 · see citing works
Prakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.029 · Cited by 104 · see citing works
Xu, F., Mu, J., Teng, Y., Zhang, X., Sundaram, K., Sriwastva, M. K., Kumar, A., Lei, C., Zhang, L., Liu, Q. M., et al. (2021) · Small · doi:10.1002/smll.202105385 · Cited by 103 · see citing works
Siglecs in Brain Function and Neurological Disorders
Siddiqui, S. S., Matar, R., Merheb, M., Hodeify, R., Vazhappilly, C. G., Marton, J., Shamsuddin, S. A., & Al Zouabi, H. (2019) · Cells · doi:10.3390/cells8101125 · Cited by 100 · see citing works
“A long-term delivery of blocking antibody against CD22 led to reversal of this phenotype in the aged brain of mice [68].”
BackgroundPhagocytic astrocytes: Emerging from the shadows of microglia
Konishi, H., Koizumi, S., & Kiyama, H. (2022) · Glia · doi:10.1002/glia.24145 · Cited by 88 · see citing works
Targeting immunosenescence and inflammaging: advancing longevity research
Nguyen, T. Q. T., & Cho, K. A. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01527-9 · Cited by 94 · see citing works
“Additionally, CD22 antibody blockade, targeting a negative regulator of microglial phagocytosis, restores immune cell function and cognitive performance in aged mice, highlighting its potential for immune rejuvenation 85 – 87 .”
Noteworthy perspectives on microglia in neuropsychiatric disorders
Zhu, H., Guan, A., Liu, J., Li, P., Zhang, Z., & Wang, S. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02901-y · Cited by 90 · see citing works
“These receptors act at different levels, including recognition, target biding, and phagosome formation [29, 134–141].”
BackgroundSocial reprogramming in ants induces longevity-associated glia remodeling
Sheng, L., Shields, E. J., Gospočić, J., Glastad, K. M., Ratchasanmuang, P., Berger, S. L., Raj, A., Little, S. C., & Bonasio, R. (2020) · Science Advances · doi:10.1126/sciadv.aba9869 · Cited by 80 · see citing works
“In mammals, glia composition and properties display developmental and age-related dynamics (44, 55, 56) including a shift to a more neuroprotective function as the brain ages (57), and restoration of the phagocytic function of microglia in aged mice improves their cognitive performance (58).”
The old guard: Age-related changes in microglia and their consequences
Costa, J., Martins, S., Ferreira, P. A., Cardoso, A. M., Guedes, J. R., Peça, J., & Cardoso, A. L. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111512 · Cited by 84 · see citing works
Lu, J., Zhang, C., Lv, J., Zhu, X., Jiang, X., Lü, W., Lu, Y., Tang, Z., Wang, J., & Shen, X. (2020) · Aging Cell · doi:10.1111/acel.13286 · Cited by 83 · see citing works
Peripheral and central neuroimmune mechanisms in Alzheimer’s disease pathogenesis
Zhang, S., Gao, Y., Zhao, Y., Huang, T. Y., Zheng, Q., & Wang, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00812-5 · Cited by 78 · see citing works
“Studies have demonstrated that CD22 functions as a negative regulator of microglial phagocytosis and is upregulated in aged microglia [123].”
InfluentialOcañas, S. R., Pham, K. D., Cox, J. E. J., Keck, A. W., Ko, S.-H., Ampadu, F. A., Porter, H. L., Ansere, V. A., Kulpa, A. M., Kellogg, C. M., et al. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02870-2 · Cited by 85 · see citing works
“CD22 was identified as a negative regulator of microglial phagocytosis in the aging brain [40] and was found to be upregulated in microglia in mouse models of AD [41].”
BackgroundSchmassmann, P., Roux, J., Buck, A., Tatari, N., Hogan, S. A., Wang, J., Mantuano, N. R., Wieboldt, R., Lee, S., Snijder, B., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adf5302 · Cited by 82 · see citing works
Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells
Baaklini, C. S., Rawji, K. S., Duncan, G. J., Ho, M. F. S., & Plemel, J. R. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00225 · Cited by 80 · see citing works
Microglia transcriptional states and their functional significance: Context drives diversity
Depp, C., Doman, J. L., Hingerl, M., Xia, J., & Stevens, B. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.009 · Cited by 81 · see citing works
Biomaterials in treatment of Alzheimer's disease
Agrawal, M., Prathyusha, E., Ahmed, H., Dubey, S. K., Kesharwani, P., Singhvi, G., Naidu, V. G. M., & Alexander, A. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105008 · Cited by 79 · see citing works
Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease
Yang, Y., & Zhang, Z. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00110 · Cited by 76 · see citing works
Anwar, S., & Rivest, S. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1738391 · Cited by 78 · see citing works
Noh, M., Kwon, H. S., Kwon, M., Nahm, M., Jin, H. K., Bae, J., & Kim, S. H. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00867-4 · Cited by 85 · see citing works
“CD22, a negative regulator of microglial phagocytosis, is elevated in plasma from AD patients as soluble CD22 [96].”
Allendorf, D. H., Puigdellívol, M., & Brown, G. C. (2019) · Glia · doi:10.1002/glia.23757 · Cited by 76 · see citing works
“…isotype + vehicle, ####p .0001 versus isotype + ST-Inh, &&&&p .0001 versus isotype + sialidase [Color figure can be viewed at wileyonlinelibrary.com] (Pluvinage et al., 2019) found that desialylation of BV-2 cells stim- ulated phagocytosis of beads, and this was attributed to Siglec-2 (sialic…”
BackgroundA novel Tmem119-tdTomato reporter mouse model for studying microglia in the central nervous system
Ruan, C., Sun, L., Kroshilina, A., Beckers, L., Jager, P. L. D., Bradshaw, E. M., Hasson, S. A., Yang, G., & Elyaman, W. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.10.009 · Cited by 71 · see citing works
Yang, J., Cao, L.-L., Wang, X.-P., Guo, W., Guo, R.-B., Sun, Y.-Q., Xue, T.-F., Cai, Z.-Y., Ji, J., Cheng, H., et al. (2021) · Cell Death & Disease · doi:10.1038/s41419-020-03310-2 · Cited by 73 · see citing works
Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning
Huo, A., Wang, J., Li, Q., Li, M., Qi, Y., Yin, Q., Luo, W., Shi, J., & Cong, Q. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.385854 · Cited by 73 · see citing works
“In addition, α2,6-linked sialic acid but not α2,3-linked sialic acid is involved in CD22-mediated inhibition of microglial phagocytosis (Pluvinage et al., 2019).”
BackgroundGonzalez-Gil, A., Porell, R. N., Fernandes, S. M., Maenpaa, E., Li, T. A., Li, T., Wong, P. C., Aoki, K., Tiemeyer, M., Yu, Z. J., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101960 · Cited by 69 · see citing works
Neuroimmune cleanup crews in brain injury
Bolte, A. C., & Lukens, J. R. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.04.003 · Cited by 68 · see citing works
Targeted glycan degradation potentiates cellular immunotherapy for solid tumors
Wu, J., Wang, X., Huang, Y., Zhang, Y., Su, S., Shou, H., Wang, H., Zhang, J., & Wang, B. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2300366120 · Cited by 69 · see citing works
Modulation of immune cell reactivity with cis -binding Siglec agonists
Delaveris, C. S., Chiu, S. H., Riley, N. M., & Bertozzi, C. R. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2012408118 · Cited by 68 · see citing works
Self-citationSialylation acts as a checkpoint for innate immune responses in the central nervous system
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Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection
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“Although CD300a is the only PS receptor known to be involved in the suppression of efferocytosis, the canonical B cell receptor CD22 has been reported as a negative regulator of phagocytosis in microglia (43).”
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Sialometabolism in Brain Health and Alzheimer’s Disease
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- Authors
- Pluvinage, J. V., Haney, M. S., Smith, B. A. H., Sun, J., Iram, T., Bonanno, L., Li, L., Lee, D. P., Morgens, D. W., Yang, A. C., Shuken, S. R., Gate, D., Scott, M., Khatri, P., Luo, J., Bertozzi, C. R., Bassik, M. C., & Wyss-Coray, T.
- Affiliations
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Nature
- Published
- 2019-04
- Volume
- 568
- Issue
- 7751
- Pages
- 187-192
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6574119
- OpenAlex
- W2934339908
- Cited by
- 459
- References
- 71
- Citations by year
- 2026: 44 · 2025: 73 · 2024: 62 · 2023: 70 · 2022: 71 · 2021: 59 · 2020: 54 · 2019: 26
- FWCI
- 23.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1s10od020141-01)
- National Institute on Aging (F30AG060638, R01AG045034, DP1AG053015)
- National Human Genome Research Institute (T32HG000044)
- National Cancer Institute (R01CA227942)
- National Institute of General Medical Sciences (T32GM120007, T32GM007365, R01GM059907)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- CD22, microglial phagocytosis, brain aging, microglial homeostasis, sialic acid, myelin debris clearance, amyloid-beta oligomers, alpha-synuclein fibrils, cognitive decline, antibody therapy, CRISPR-Cas9 screen, neurodegeneration
- MeSH terms
- CRISPR-Associated Protein 9, Aging, Animals, Brain, Cognition, Female, Homeostasis, Male, Mice, Inbred C57BL, Phagocytosis, Sequence Analysis, RNA, Microglia, N-Acetylneuraminic Acid, Mice, Sialic Acid Binding Ig-like Lectin 2, CRISPR-Cas Systems
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