Prof. Guojun Bu is currently the Lo Ka Chung Charitable Foundation Professor of Science and a Chair Professor in the Division of Life Science at the Hong Kong University of Science and Technology. Prof. Bu received his PhD degree in Biochemistry from Virginia Tech and completed his postdoctoral training at the Washington University School of Medicine in St. Louis with a focus in cell biology and neuroscience. His previous career appointments include the Chair of the Department of Neuroscience and a named professor at Mayo Clinic, the Chief Scientific Officer of SciNeuro Pharmaceuticals, and a Professor of Cell Biology and Neuroscience at the Washington University in St. Louis.

Prof. Bu is a world leader in the field of apoE and apoE receptors, which play critical roles in the pathogenesis of Alzheimer’s disease and related dementias. He has published >350 high impact articles with an H-index of 115, i10-index of 302, and ~40,000 citations (Google Scholar). He has been a “Highly Cited Researcher” according to Web of Science for the past several years. Prof. Bu has received numerous honors and awards including the Zenith Fellows Award from the Alzheimer’s Association, the Established Investigator Award from the American Heart Association, a MERIT award from NIH, the Investigator of the Year award from the Mayo Clinic, and the MetLife Foundation Award for Medical Research in Alzheimer’s disease. He is an elected Fellow of the American Association for the Advancement of Science (AAAS), Founding Editor and Editor-in-Chief of Molecular Neurodegeneration, an Associate Editor for Science Advances, and is on the editorial board for Neuron.

Research Question

Prof. Bu’s primary interest is to understand why APOE4 is a strong genetic risk factor for Alzheimer’s disease and how this gene and related molecular pathways can be targeted for therapy. His interests also extend to addressing the protective mechanisms of APOE2 and APOE rare variants. Among the pathogenic pathways contributing to aging and Alzheimer’s disease, Prof. Bu’s work addresses the roles of brain lipid metabolism, neuronal signaling, neuroimmune focusing on TREM2 and APOE, mechanisms of proteinopathy, and cerebrovascular integrity and function.

Research Approach

APOE and APOE receptor LRPs play critical roles in lipid metabolism, protein trafficking, and signaling. Prof. Bu’s early work using cell biological approaches unraveled the mechanisms of biogenesis and endocytic trafficking of LRP1, a large endocytic receptor with >30 ligands including APOE, amyloid-b (Ab), tau, and a-synuclein, all are critically involved in the pathogenesis of Alzheimer’s and other neurodegenerative diseases. His lab had systematically dissected the cell type-specific function of LRP1 using conditional mouse models as it relates to brain Ab clearance, lipid metabolism, and cerebrovascular function. Prof. Bu’s work also extends to other members of the LDL receptor family including LRP1B and LRP6, as well as insulin receptor. While LRP6 is a key canonical Wnt signaling receptor involved in synaptic function and brain Ab metabolism, the insulin receptor modulates glucose metabolism and mitochondrial functions in aging and Alzheimer’s disease. Prof. Bu’s work in the past 15 years has been focused more on the pathogenic mechanisms of APOE4 using humanized mouse models, as well as induced pluripotent stem cell (iPSC) models including cerebral organoids. Using amyloid model mice, his lab discovered that APOE4 seeds amyloids, considered to be the driving mechanism for the development of Alzheimer’s disease. Using conditional mouse models expressing APOE isoforms in a cell type-specific and inducible manner, Prof. Bu’s lab has also demonstrated the detrimental effects of APOE4 expressed in vascular cells, microglia, or periphery, revealing the multifactorial effects of APOE4 in the pathogenesis of Alzheimer’s disease. Also using humanized APOE mouse models, his lab described the critical role of APOE2 and APOE3-Jacksonville variant in enhancing brain lipid metabolism and cognition, leading to protection against Alzheimer’s disease. Complementing their model system studies, Prof. Bu’s group also utilizes human biospecimens including postmortem brains, cerebral spinal fluid (CSF), and plasma samples to both discover new pathways and biomarkers, and to validate outcomes from model system studies. Prof. Bu’s current work continues to focus on addressing the pathogenic mechanisms of APOE4 and the protective mechanisms of APOE2. His lab is also devoting significant efforts to discovering and developing therapeutics toward APOE and other targets with a goal to prevent and cure Alzheimer’s disease.

Recent Representative Publications

1. Liu C-C, Wang N, Chen Y, Inoue Y, Shue F, Ren Y, Wang M, Qiao W, Ikezu TC, Li Z, Zhao J, Martens Y, Doss SV, Rosenberg CL, Jeevaratnam S, Jia L, Raulin A-C, Qi F, Zhu Y, Alnobani A, Knight J, Chen Y, Linares, Kurti A, Fryer JD, Zhang B, Wu L-J, Kim BYS, Bu G. Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer’s disease. Nat Immunology 2023; In press.
2. Liu C-C, Zhao J, Fu Y, Inoue Y, Ren Y, Chen Y, Doss SV, Shue F, Jeevaratnam S, Bastea L, Wang N, Martens YA, Qiao W, Wang M, Zhao N, Jia L, Yamazaki Y, Yamazaki A, Rosenberg CL, Wang Z, Kong D, Kuchenbecker LA, Li Z, Trottier ZA, Felton L, Rogers J, Quicksall ZS, Linares C, Knight J, Chen Y, Kurti A, Kanekiyo T, Fryer JD, Asmann YW, Storz P, Wang X, Peng J, Zhang B, Kim BYS, Bu G. Peripheral apoE4 impairs brain cognition and enhances Alzheimer’s pathology by compromising cerebrovascular function. Nat Neurosci 2022; 25:1020-1033. PMCID: PMC10009873.
3. Raulin AC, Martens YA, Bu G.  Lipoproteins in the central nervous system: From biology to pathobiology. Annu Rev Biochem 2022; 91:731-759. PMID: 35303786.
4. Liu CC, Murray ME, Li X, Zhao N, Wang N, Heckman MG, Shue F, Martens Y, Li Y, Raulin AC, Rosenberg CL, Doss SV, Zhao J, Wren MC, Jia L, Ren Y, Ikezu TC, Lu W, Fu Y, Caulfield T, Trottier ZA, Knight J, Chen Y, Linares C, Wang X, Kurti A, Asmann YW, Wszolek ZK, Smith GE, Vemuri P, Kantarci K, Knopman DS, Lowe VJ, Jack CR Jr, Parisi JE, Ferman TJ, Boeve BF, Graff-Radford NR, Petersen RC, Younkin SG, Fryer JD, Wang H, Han X, Frieden C, Dickson DW, Ross OA, Bu G. APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Sci Transl Med 2021; 13 (613):eabc9375. PMCID: PMC8824726.
5. Zhao N, Attrebi ON, Ren Y, Qiao W, Sonustun B, Martens YA, Meneses AD, Li F, Shue F, Zheng J, Van Ingelgom AJ, Davis MD, Kurti A, Knight JA, Linares C, Chen Y, Delenclos M, Liu C-C, Fryer JD, Asmann YW, McLean PJ, Dickson DW, Ross OA, and Bu G. APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Sci Transl Med 2020; 12(529), eaay1809. PMCID: PMC8309690.
6. Zhao J, Fu Y, Yamazaki Y, Ren Y, Davis MD, Liu CC, Lu W, Wang X, Chen K, Cherukuri Y, Jia L, Martens YA, Job L, Shue F, Nguyen TT, Younkin SG, Graff-Radford NR, Wszolek ZK, Brafman DA, Asmann YW, Ertekin-Taner N, Kanekiyo T, Bu G. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids. Nat Commun 2020; 11(1):5540. doi: 10.1038/s41467-020-19264-0. PMCID: PMC8500881.
7. Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 2019; 15(9):501-518. PMCID: PMC7055192.
8. Yamazaki Y, Shinohara M, Shinohara M, Yamazaki A, Murray ME, Liesinger AM, Heckman MG, Lesser ER, Parisi JE, Petersen RC, Dickson DW, Kanekiyo T, Bu G. Selective loss of cortical endothelial tight junction proteins during Alzheimer’s disease progression. Brain 2019; 142(4):1077-1092. doi: 10.1093/brain/awz011. PMCID: PMC6439325.
9. Zhao N, Liu CC, Van Ingelgom AJ, Linares C, Kurti A, Knight JA, Heckman MG, Diehl NN, Shinohara M, Martens YA, Attrebi ON, Petrucelli L, Fryer JD, Wszolek ZK, Graff-Radford NR, Caselli RJ, Sanchez-Contreras MY, Rademakers R, Murray ME, Koga S, Dickson DW, Ross OA, Bu G. APOE ε2 is associated with increased tau pathology in primary tauopathy. Nat Commun 2018; 9(1):4388. doi: 10.1038/s41467-018-06783-0. PMCID: PMC6197187.
10. Zhao N, Liu CC, Van Ingelgom AJ, Martens YA, Linares C, Knight JA, Painter MM, Sullivan PM, Bu G. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron 2017; 96:115-129. PMCID: PMC5621659.
11. Liu C-C, Zhao N, Yamaguchi Y, Cirrito JR, Kanekiyo T, Holtzman DM, Bu G. Neuronal heparan sulfates promote amyloid pathology by impairing the clearance and accelerating the aggregation of amyloid-β in Alzheimer’s disease. Sci Transl Med 2016; 8:332ra44. PMCID: PMC5512541.