. Associations of plasma soluble CD22 levels with brain amyloid burden and cognitive decline in Alzheimer's disease. Sci Adv. 2022 Apr;8(13):eabm5667. PubMed.


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  1. Wyss-Coray and colleagues previously reported that microglia in aged mice express CD22, which functions as an inhibitory receptor of phagocytosis (Pluvinage et al., 2019). Although their follow-up study (Pluvinage et al., 2021) did not find expression of CD22 in human microglia, they found that human oligodendrocytes release soluble CD22 (sCD22) which binds to IGF2R on microglia and that this interaction negatively regulates lysosomal activity of microglia. Whether sCD22 derived from other cell types may contribute to the lysosome dysfunction in microglia remains unclear.

    In the present study, Bu et al. demonstrate an inverse correlation between plasma sCD22 and cognitive function in patients with preclinical Alzheimer’s disease. Consistent with this finding, the authors also found plasma sCD22 levels positively correlate with phosphorylated tau levels and brain Aβ burden. This interesting finding suggests that sCD22 may be a potential biomarker for Alzheimer's disease.

    At the same time, it raises the question of whether plasma sCD22 is solely provided by oligodendrocytes, by microglia or other cells. According to the literature and the Human Protein Atlas, human CD22 is expressed by oligodendrocytes, B cells, and Sertoli cells. Since B cells are particularly abundant in the blood, it’s critical to understand whether B cells contribute to plasma sCD22.

    In addition, recent studies have revealed that meninges are niches for de novo B cell lymphopoiesis (Brioschi et al., 2021; Schafflick et al., 2021; Wang et al., Immunity 2021). Thus, meningeal B cells might be a potential source of sCD22 in the cerebral spinal fluid.

    Another interesting question for future studies is whether B cell-derived sCD22 is not only a marker, but actively impacts the pathogenesis of Alzheimer’s disease, regulating other cells in the CNS that express putative receptors for sCD22.


    . CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature. 2019 Apr;568(7751):187-192. Epub 2019 Apr 3 PubMed.

    . The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C. Sci Transl Med. 2021 Dec;13(622):eabg2919. PubMed.

    . Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science. 2021 Jun 3; PubMed.

    . Single-cell profiling of CNS border compartment leukocytes reveals that B cells and their progenitors reside in non-diseased meninges. Nat Neurosci. 2021 Sep;24(9):1225-1234. Epub 2021 Jul 12 PubMed.

    . Early developing B cells undergo negative selection by central nervous system-specific antigens in the meninges. Immunity. 2021 Dec 14;54(12):2784-2794.e6. Epub 2021 Oct 8 PubMed.

  2. Multiple cell types contribute to AD pathogenesis. Biomarkers tracking each of these cell types will be critical for detecting AD sooner, illuminating disease heterogeneity, and designing clinical trials for next-generation therapeutics. In this exciting new study, the authors provide evidence that soluble CD22 (sCD22), a potent inhibitor of microglial function, is a potential biomarker of early cognitive decline in AD.

    We previously found that CD22 impairs cognitive function in mice, and sCD22 released by oligodendrocytes blocks lysosome function in human microglia models (Pluvinage et al., 2019). This paper builds off these preclinical studies to show that plasma sCD22 levels are increased in AD patients. Specifically, plasma sCD22 rises at the preclinical stage of AD and negatively correlates with cognitive function.

    While the use of two geographically distinct patient cohorts is a particular strength of this study, the reported correlations of sCD22 with amyloid and tau biomarkers are relatively loose. Because sCD22 rises at the pre-symptomatic stage, future comparisons to other pre-symptomatic biomarkers such as neurofilament light chain (NfL) will be informative. Furthermore, it will be important to measure sCD22 levels in CSF to determine if plasma sCD22 truly reflects changes in the brain.

    Overall, this study introduces a new pre-symptomatic AD biomarker with direct links to microglial function. These findings not only support sCD22 as a new diagnostic tool, but also suggest sCD22 is a potential therapeutic target in AD akin to our findings in lysosomal storage disease.

    Combined with other emerging cell-type specific biomarkers such as NfL (Preische et al., 2019) and soluble TREM2 (Morenas-Rodriguez et al., 2022), measurement of sCD22 may provide a more nuanced, non-invasive view into the natural history and therapeutic modification of AD.


    . CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature. 2019 Apr;568(7751):187-192. Epub 2019 Apr 3 PubMed.

    . Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med. 2019 Feb;25(2):277-283. Epub 2019 Jan 21 PubMed.

    . Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study. Lancet Neurol. 2022 Apr;21(4):329-341. PubMed.

  3. We thank Drs. Colonna, Wang, and Pluvinage for their comments. Our study found that plasma sCD22 was increased at early stages of AD, and its level was positively correlated with brain Aβ burden, CSF p-tau levels, and longitudinal cognitive decline. It provides human evidence to support critical roles of CD22 in AD pathogenesis, suggesting that sCD22 may be a potential diagnostic biomarker and therapeutic target for AD.

    Some questions still need to be answered. Human CD22 is expressed by several cell types, including oligodendrocytes, B cells, and Sertoli cells (Poe and Tedder, 2012; Pluvinage et al., 2021; Human Protein Atlas). It is critical to clarify the source of plasma sCD22, which determines the correlations of plasma sCD22 and AD observed in our study. Since B cells are abundant in the blood, it is worth investigating whether B cell-derived sCD22 is not only a marker but also involved in AD pathogenesis.

    There is an urgent need to find biomarkers to reflect the functional status of microglia in the brain (Hampel et al., 2021). The alterations of sCD22 levels in the brain of AD are unknown. It is necessary to investigate whether plasma sCD22 levels accurately reflect sCD22 levels in the brain or CSF and, more importantly, whether plasma sCD22 is a potential biomarker to reflect microglial function in AD.

    A recent study found that sCD22 impairs the microglial lysosome function, and blocking the interaction between sCD22 and microglia improved lysosome function in human pluripotent-stem-cell–derived microglia-like cells (Pluvinage et al., 2021). It is also suggested that CD22 is involved in the age-related microglial impairment and CD22 blockade restores homeostatic microglial phagocytosis in aging brains (Pluvinage et al., 2019). These findings put forward a question of whether CD22 is a therapeutic target for AD. Future studies are warranted to fully understand the roles of CD22 and sCD22 in AD pathogenesis and their therapeutic potentials.


    . Developing the ATX(N) classification for use across the Alzheimer disease continuum. Nat Rev Neurol. 2021 Sep;17(9):580-589. Epub 2021 Jul 8 PubMed.

    . CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature. 2019 Apr;568(7751):187-192. Epub 2019 Apr 3 PubMed.

    . The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C. Sci Transl Med. 2021 Dec;13(622):eabg2919. PubMed.

    . CD22 and Siglec-G in B cell function and tolerance. Trends Immunol. 2012 Aug;33(8):413-20. Epub 2012 Jun 5 PubMed.

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