Yingyue Zhou

All Publications

• Mutations in the human CSF1R gene impact microglia's maintenance of brain white matter integrity. Nature immunology Du, S., Zhou, Y., Li, D., Lier, J., Cella, M., Tada, M., Hamasaki, H., Wu, J., Cai, Z., Orthmann-Murphy, J. L., Kakita, A., Kipnis, J., Bergner, C. G., Colonna, M. 2025

  Abstract

  Microglia, the brain's resident macrophages, depend on interleukin-34 and colony-stimulating factor 1 (CSF1) for their development and maintenance, engaging the CSF1 receptor (CSF1R). Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disorder affecting the brain's white matter, is caused by heterozygous pathogenic mutations in the CSF1R gene. This study investigated molecular mechanisms underlying ALSP using single-nucleus RNA sequencing on postmortem brain specimens. Results showed a significant reduction in microglia in ALSP brains, with remaining cells exhibiting a unique activation signature. This reduction correlated with decreased myelinating oligodendrocytes (OLs) and increased neuropilin-2+ OLs with a stress-response and anti-apoptotic signature, driven by STAT3 and fibroblast growth factor receptor pathways. Additionally, astrocytes displayed maladaptive activation and stress responses. These findings underscore microglia's crucial role in supporting OL myelination and limiting astrocyte repair responses, suggesting therapeutic strategies balancing CSF1R, fibroblast growth factor receptor and STAT3 pathways for ALSP and other genetically caused microgliopathies.

  View details for DOI 10.1038/s41590-025-02195-7

  View details for PubMedID 40571738

• Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control. The Journal of experimental medicine Cai, Z., Wang, S., Cao, S., Chen, Y., Penati, S., Peng, V., Yuede, C. M., Beatty, W. L., Lin, K., Zhu, Y., Zhou, Y., Colonna, M. 2025; 222 (4)

  Abstract

  Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer's disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age.

  View details for DOI 10.1084/jem.20230173

  View details for PubMedID 39945772

• Targeting TREM2 signaling shows limited impact on cerebrovascular calcification LIFE SCIENCE ALLIANCE Sridhar, S., Zhou, Y., Ibrahim, A., Bertazzo, S., Wyss, T., Swain, A., Maheshwari, U., Huang, S., Colonna, M., Keller, A. 2024; 8 (1)

  Abstract

  Brain calcification, the ectopic mineral deposits of calcium phosphate, is a frequent radiological finding and a diagnostic criterion for primary familial brain calcification. We previously showed that microglia curtail the growth of small vessel calcification via the triggering receptor expressed in myeloid 2 (TREM2) in the Pdgfb ret/ret mouse model of primary familial brain calcification. Because boosting TREM2 function using activating antibodies has been shown to be beneficial in other disease conditions by aiding in microglial clearance of diverse pathologies, we investigated whether administration of a TREM2-activating antibody could mitigate vascular calcification in Pdgfb ret/ret mice. Single-nucleus RNA-sequencing analysis showed that calcification-associated microglia share transcriptional similarities to disease-associated microglia and exhibited activated TREM2 and TGFβ signaling. Administration of a TREM2-activating antibody increased TREM2-dependent microglial deposition of cathepsin K, a collagen-degrading protease, onto calcifications. However, this did not ameliorate the calcification load or alter the mineral composition and the microglial phenotype around calcification. We therefore conclude that targeting microglia with TREM2 agonistic antibodies is insufficient to demineralize and clear vascular calcifications.

  View details for DOI 10.26508/lsa.202402796

  View details for Web of Science ID 001344022800001

  View details for PubMedID 39467636

  View details for PubMedCentralID PMC11519321

• Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model SCIENCE TRANSLATIONAL MEDICINE Hou, J., Chen, Y., Cai, Z., Heo, G., Yuede, C. M., Wang, Z., Lin, K., Saadi, F., Trsan, T., Nguyen, A. T., Constantopoulos, E., Larsen, R. A., Zhu, Y., Wagner, N. D., McLaughlin, N., Kuang, X., Barrow, A. D., Li, D., Zhou, Y., Wang, S., Gilfillan, S., Gross, M. L., Brioschi, S., Liu, Y., Holtzman, D. M., Colonna, M. 2024; 16 (741): eadj9052

  Abstract

  Microglia help limit the progression of Alzheimer's disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia wrapping around Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ load, mitigated some Aβ-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.

  View details for DOI 10.1126/scitranslmed.adj9052

  View details for Web of Science ID 001198870500003

  View details for PubMedID 38569016

• Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination. Cell reports Hou, J., Zhou, Y., Cai, Z., Terekhova, M., Swain, A., Andhey, P. S., Guimaraes, R. M., Ulezko Antonova, A., Qiu, T., Sviben, S., Strout, G., Fitzpatrick, J. A., Chen, Y., Gilfillan, S., Kim, D. H., Van Dyken, S. J., Artyomov, M. N., Colonna, M. 2023; 42 (4): 112293

  Abstract

  Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFBhi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.

  View details for DOI 10.1016/j.celrep.2023.112293

  View details for PubMedID 36952346

  View details for PubMedCentralID PMC10511667

• Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia. Nature immunology Zhou, Y., Tada, M., Cai, Z., Andhey, P. S., Swain, A., Miller, K. R., Gilfillan, S., Artyomov, M. N., Takao, M., Kakita, A., Colonna, M. 2023; 24 (3): 545-557

  Abstract

  The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-β signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.

  View details for DOI 10.1038/s41590-022-01403-y

  View details for PubMedID 36658241

  View details for PubMedCentralID PMC9992145

• TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis JOURNAL OF CLINICAL INVESTIGATION Hou, J., Zhang, J., Cui, P., Zhou, Y., Liu, C., Wu, X., Ji, Y., Wang, S., Cheng, B., Ye, H., Shu, L., Zhang, K., Wang, D., Xu, J., Shu, Q., Colonna, M., Fang, X. 2021; 131 (4)

  Abstract

  Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.

  View details for DOI 10.1172/JCI135197

  View details for Web of Science ID 000620158600004

  View details for PubMedID 33586673

  View details for PubMedCentralID PMC7880419

• Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. Nature medicine Zhou, Y., Song, W. M., Andhey, P. S., Swain, A., Levy, T., Miller, K. R., Poliani, P. L., Cominelli, M., Grover, S., Gilfillan, S., Cella, M., Ulland, T. K., Zaitsev, K., Miyashita, A., Ikeuchi, T., Sainouchi, M., Kakita, A., Bennett, D. A., Schneider, J. A., Nichols, M. R., Beausoleil, S. A., Ulrich, J. D., Holtzman, D. M., Artyomov, M. N., Colonna, M. 2020; 26 (1): 131-142

  Abstract

  Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

  View details for DOI 10.1038/s41591-019-0695-9

  View details for PubMedID 31932797

  View details for PubMedCentralID PMC6980793

• ApoE facilitates the microglial response to amyloid plaque pathology JOURNAL OF EXPERIMENTAL MEDICINE Ulrich, J. D., Ulland, T. K., Mahan, T. E., Nystrom, S., Nilsson, K., Song, W. M., Zhou, Y., Reinartz, M., Choi, S., Jiang, H., Stewart, F. R., Anderson, E., Wang, Y., Colonna, M., Holtzman, D. M. 2018; 215 (4): 1047-1058

  Abstract

  One of the hallmarks of Alzheimer's disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1ΔE9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aβ morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.

  View details for DOI 10.1084/jem.20171265

  View details for Web of Science ID 000440817800006

  View details for PubMedID 29483128

  View details for PubMedCentralID PMC5881464

• TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease CELL Ulland, T. K., Song, W. M., Huang, S., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y., Caims, N. J., Kambal, A., Loginicheva, E., Gilfillan, S., Cella, M., Virgin, H. W., Unanue, E. R., Wang, Y., Artyomov, M. N., Holtzman, D. M., Colonna, M. 2017; 170 (4): 649-+

  Abstract

  Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.

  View details for DOI 10.1016/j.cell.2017.07.023

  View details for Web of Science ID 000407445700007

  View details for PubMedID 28802038

  View details for PubMedCentralID PMC5573224