Education

BS (eq)
Tsinghua University, Beijing, China Major: Biological Science
PhD
University of North Carolina at Chapel Hill, Major: Biochemistry
Postdoctoral Fellowship
The Scripps Research Institute, Subject: Molecular Virology

Areas of Interest

Research Interests

My lab’s research focuses on neuroinflammation accompanying neurodegenerative processes, esp. Alzheimer’s disease (AD). In the past decade, neuroinflammation is increasingly recognized as a major contributor to the pathogenesis of a wide range of neurological diseases.

By analyzing multiple disease models, we have dissected AD-associated inflammatory responses and identified an intrinsic antiviral response at the core of microglia-mediated brain inflammation. The key cytokine involved is type I interferon (IFN), which pathogenically promotes synapse elimination and impairs memory performance. Our research discovered a prominent activation of the IFN pathway in human AD brains, implying a clinical relevance of the novel findings. We are continuing studies to fully comprehend how interferon partakes in neuropathology during AD progression in various disease models. In addition, we are probing the involvement of other inflammatory and physiological pathways in brain cell crosstalk and signaling regulation under AD-relevant conditions.

Aging represents the most important factor endorsing neurodegeneration. By no coincidence, the aging brain manifests with elevated neuroinflammation, which contributes to cognitive decline. What initiates such an inflammatory response is unclear at the moment. We are keen to investigate whether genomic instability, a hallmark of aging, can cause innate immune response thus leading to neuroinflammation in AD as well as brain aging. In particular, we are examining the dysregulation of transposable elements, which constitute a large portion of the genome, in the central nervous system. We believe that the fundamental understanding of neuroinflammation will help decipher the underlying pathogenic processes in many diseases.

Neurodegeneration is NOT a disease restricted to the brain. Systemic changes and environmental factors, ranging from gut microbiota, metabolic diseases, inflammatory conditions, diet and exercise, can profoundly influence the onset and progression of AD in many ways. Hence, we are examining the role played by peripheral responses or external disturbances in modifying brain inflammation and pathologies. A broad research perspective and approach will allow us to obtain deeper insights into the key factors driving neurodegeneration.

Publications

Selected Publications

  1. Roy, E. and Cao, W. (2022). Glial interference: impact of type I interferon in neurodegenerative diseases. Mol Neurodegener 17: 78.
  2. Zhao P, Xu Y, Jiang L, Fan X, Li L, Li X, Arase H, Zhao Y, Cao W, Zheng H, Xu H, Tong Q, Zhang N, and An Z.  (2022) A tetravalent TREM2 agonistic antibody with αTfR-mediated brain entry for the reduction of amyloid pathology in 5XFAD mice. Sci Transl Med, 14, eabq0095. PMID: 36070367.
  3. Roy E., Chiu G, Li S, Propson NE, Zheng H, Cao W (2022) Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques. Immunity, 55:897-894. PMID: 35443157
  4. Cao W (2022)  IFN-aging: coupling aging with interferon response. Front Aging, 3: 870489 PMID: 35821859
  5. Ramirez P, Zuniga G, Sun W, Beckmann A, Ochoa E, Devos S, Hyman B, Chiu G, Roy ER, Cao W., Orr M, Buggia-Prevot V, Ray WJ, and Frost B (2022). Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system, Prog Neurobiol 208:102181. PMID: 34670118
  6. Roy ER, and Cao W (2020) Antiviral Immune Response in Alzheimer’s Disease: Connecting the Dots. Front Neurosci.14:577744. PMID: 33132831
  7. Roy ER, Wang B, Wan Y-W, Chiu GS, Cole AL, Yin Z, Propson NE, Xu Y, Jankowsky JL, Liu Z, Lee VMY, Trojanowski JQ, Ginsberg SD, Butovsky O, Zheng H, and Cao W (2020) Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. J Clin Invest. 130:1912-30. PMID: 31917687
  8. Cao W, Zheng H (2018). Peripheral immune system in aging and Alzheimer’s disease. Mol Neurodegener. 13: 51. Pubmed PMID: 30285785
  9. Huang X, Li J, Dorta-Estremera S, Di Domizio J, Anthony SM, Watowich SS, Popkin D, Liu Z, Brohawn P, Yao Y, Schluns KS, Lanier LL, Cao W. (2015)  Neutrophils Regulate Humoral Autoimmunity by Restricting Interferon-γ Production via the Generation of Reactive Oxygen Species. Cell Rep 12:1120-32. PMID: 26257170
  10. Cao, W (2014) Pivotal functions of plasmacytoid dendritic cells in systemic autoimmune pathogenesis. J Clin Cell Immunol, 5:e212. PMID: 25077037
  11. Di Domizio J, Dorta-Estremera S, Gagea M, Ganguly D, Miller D, Li P, Zhao B, Tan FK, Bi L, Gilliet M, and Cao W (2012) Nucleic Acid-Containing Amyloid Fibrils Potently Induce Type I Interferon and Stimulate Systemic Autoimmunity. Proc. Natl. Acad. Sci. USA 109: 14550-5. PMID: 22904191
  12. Di Domizio, J, Zhang R, Stagg LJ, Gagea M, Zhuo M, Ladbury JE, and Cao W. (2012). Binding with Nucleic Acids or Glycosaminoglycans Converts Soluble Protein Oligomers to Amyloid. J Biol Chem 287: 736-747. PMID: 22102410
  13. Cao W, Bover L. (2010). Signaling and ligand interaction of ILT7: receptor-mediated regulatory mechanisms for plasmacytoid dendritic cells. Immunol Rev. 234:163-76. PMID: 20193018
  14. Gilliet M*, Cao W*, and Liu Y-J. (2008) Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Imm 8: 594-606. PMID: 18641647 (*equal contribution)
  15. Cao W. (2009). Molecular Characterization of Human Plasmacytoid Dendritic Cells. J Clin Immunol.  29:257-64. PMID: 19266271
  16. Cao W, Bover L, Cho M, Wen X, Hanabuchi S, Bao M, Rosen DB, Wang Y-H, Shaw JL, Du Q, Li C, Arai N, Yao Z, Lanier LL & Liu Y-J. (2009). Regulation of TLR7/9 Responses in Plasmacytoid Dendritic Cells by BST2 and ILT7 Receptor Interaction. J. Exp. Med, 206:1603-14. PMID: 19564354
  17. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang Y-H, Homey B, Cao W, Wang Y-H, Su B, Nestle FO, Zal T, Mellman I, Schroder J-M, Liu Y-J, Gilliet M. (2007). Plasmacytoid dendritic cells sense self-DNA coupled with an antimicrobial peptide. Nature 449:564-9. PMID: 17873860
  18. Cao W, Zhang L, Rosen DB, Bover L, Watanabe G, Bao M, Lanier LL, Liu Y-J.. (2007). BDCA2 and FceRIg Complex Signals through a Novel BCR-like Pathway in Human Plasmacytoid Dendritic Cells. PLoS Biology 5: e248. PMID: 17850179
  19. Cao W, Rosen DB, Ito T, Bover L, Bao M, Watanabe G, Zhang L, Lanier LL, Liu Y-J.. (2006). Plasmacytoid Dendritic Cell-Specific Receptor ILT7/FceRIg Inhibits Toll-Like Receptor-Induced Interferon Production. J. Exp. Med. 203:1399-1405. PMID: 16735691
  20. Watanabe N, Wang Y-H, Lee HK, Ito T, Wang Y-H, Cao W, Liu Y-J. (2005). Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436:1181-5. PMID: 16121185
  21. Cao W, Henry MD, Borrow P, Yamada H, Elder JH, Ravkov EV, Nichol ST, Compans RW, Campbell KP, Oldstone MBA. (1998). Identification of a-dystroglycan as a receptor for Lymphocytic Choriomeningitis Virus and Lassa Fever Virus. Science 282: 2079-208. PMID: 9851928