YE Keqiang

YE Keqiang

Ph.D, Professor, Principal investigator
Molecular mechanisms in neurodegenerative diseases, early diagnosis and drug development
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Research

Dr. Ye is the recipient of numerous professional honors, including the Distinguished Scientist Award from the Sontag Foundation (2003) and American Cancer Research Scholar (2004), and he is also one of the semi-finalists for Keck Foundation (2004). He has published approximately 220 papers with numerous papers in top journals including: Cell, Nature, Nature Medicine, Nature Cell Biology, Nature Neuroscience, Neuron, Mol. Cell, EMBO J, PNAS etc. His lab mainly focuses on neurotrophine-mediated neuronal survival singaling pathway and their role in neurodegenerative diseases. He identified numerous novel TrkA and TrkB agonists. These small molecules exhibit potent neurotrophic effect and display great therapeutic potentials for various neurological diseases including Alzheimer’s disease (AD). Most recently, he found that AEP acts as a novel delta-secretase that cleaves both APP and Tau and mediates AD pathogenesis. It is an innovative drug target for treating AD. His lab has identified the small molecular inhibitors that display promising therapeutic efficacy toward AD.


Biography

2021-Present,  Department Chair, Chair Professor, Faculty of Life and Health Sciences, SIAT

2010-2021,      Tenured Full Professor, Department of Pathology and Laboratory Medicine,

                         Emory University School of Medicine

2007-2010,      Tenured Associate Professor, Department of Pathology and Laboratory Medicine,

                         Emory University School of Medicine

2001-2007,       Assistant Professor, Department of Pathology and Laboratory Medicine, Emory University School of Medicine

1998-2001,       Postdoctoral Fellow, Department of Neuroscience The Johns Hopkins University School of Medicine, Baltimore,

                         MD 21205 Supervisor: Solomon H. Snyder, MD

1993-1998,       Ph.D. in Biochemistry and Cell Biology, Emory University, Atlanta, Georgia 30322,

                         Supervisor: Harish C. Joshi, Ph.D.

1990-1993,       M.S. in Chemistry Peking University, Beijing, China

1986-1990,       B.S. in Chemistry Jilin University, Changchun, China


Selected publications

  1. Xia, Y.; Qadota, H.; Wang, ZH.; Liu P.; Xia Liu.; Ye, KX.; Matheny, CJ.; Berglund, K.; Yu, SP.; Drake, D.; Bennett, DA.; Wang, XC.; Yankner, BA.; Benian, GM and Ye, K. Neuronal C/EBPβ/AEP Pathway Shortens Lifespan via Selective GABAnergic Neuronal Degeneration by FOXO Repression. SCIENCE ADVANCES. 2022, (In Press)

  1. Kang, SS.; Meng, L.; Zhang, X.; Wu, Z.; Mancieri, A.; Xie, B.; Liu, X.; Weinshenker, D.; Peng, J.; Zhang, Z and Ye, K. Tau Modification by the Noradrenaline Metabolite DOPEGAL Stimulates its Pathology and Propagation. NATURE STRUCTURAL & MOLECULAR BIOLOGY. 2022, (In Press)

  1. Xiong, J.; Kang, S. S.; Wang, Z.; Liu, X.; Kuo, T. C.; Korkmaz, F.; Padilla, A.; Miyashita, S.; Chan, P.; Zhang, Z.; Katsel, P.; Burgess, J.; Gumerova, A.; Ievleva, K.; Sant, D.; Yu, S. P.; Muradova, V.; Frolinger, T.; Lizneva, D.; Iqbal, J.; Goosens, K. A.; Gera, S.; Rosen, C. J.; Haroutunian, V.; Ryu, V.; Yuen, T.; Zaidi, M.; Ye, K. FSH blockade improves cognition in mice with Alzheimer's disease. NATURE. 2022.

  1. Wang, Z. H.; Xia, Y.; Wu, Z.; Kang, S. S.; Zhang, J. C.; Liu, P.; Liu, X.; Song, W.; Huin, V.; Dhaenens, C. M.; Yu, S. P.; Wang, X. C.; Ye, K. Neuronal ApoE4 stimulates C/EBPbeta activation, promoting Alzheimer's disease pathology in a mouse model. PROGRESS IN NEUROBIOLOGY. 2022, 209, 102212.

  1. Chen, G.; Ahn, E. H.; Kang, S. S.; Xia, Y.; Liu, X.; Zhang, Z.; Ye, K. UNC5C Receptor Proteolytic Cleavage by Active AEP Promotes Dopaminergic Neuronal Degeneration in Parkinson's Disease. ADVANCED SCIENCE. 2022, 9, e2103396.

  1. Chen, C.; Liao, J.; Xia, Y.; Liu, X.; Jones, R.; Haran, J.; McCormick, B.; Sampson, T. R.; Alam, A.; Ye, K. Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation. GUT. 2022.

  1. Yao, Y.; Kang, S. S.; Xia, Y.; Wang, Z. H.; Liu, X.; Muller, T.; Sun, Y. E.; Ye, K. A delta-secretase-truncated APP fragment activates CEBPB, mediating Alzheimer's disease pathologies. BRAIN. 2021, 144, 1833-1852.

  1. Kang, S. S.; Ahn, E. H.; Liu, X.; Bryson, M.; Miller, G. W.; Weinshenker, D.; Ye, K. ApoE4 inhibition of VMAT2 in the locus coeruleus exacerbates Tau pathology in Alzheimer's disease. ACTA NEUROPATHOLOGICA. 2021, 142, 139-158.

  1. Xia, Y.; Wang, Z. H.; Liu, P.; Edgington-Mitchell, L.; Liu, X.; Wang, X. C.; Ye, K. TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer's disease pathologies. MOLECULAR PSYCHIATRY. 2021, 26, 2943-2963.

  1. Wu, Z. R.; Xia, Y. Y.; Wang, Z. H.; Kang, S. S.; Lei, K. C.; Liu, X.; Jin, L. J.; Wang, X. C.; Cheng, L. M.; Ye, K. C/EBP beta/delta-secretase signaling mediates Parkinson's disease pathogenesis via regulating transcription and proteolytic cleavage of alpha-synuclein and MAOB. MOLECULAR PSYCHIATRY. 2021, 26, 568-585.

  1. Chen, G.; Kang, S. S.; Wang, Z.; Ahn, E. H.; Xia, Y.; Liu, X.; Sandoval, I. M.; Manfredsson, F. P.; Zhang, Z.; Ye, K. Netrin-1 receptor UNC5C cleavage by active delta-secretase enhances neurodegeneration, promoting Alzheimer's disease pathologies. SCIENCE ADVANCES. 2021, 7.

  1. Chen, C.; Zhou, Y.; Wang, H.; Alam, A.; Kang, S. S.; Ahn, E. H.; Liu, X.; Jia, J.; Ye, K. Gut inflammation triggers C/EBPbeta/delta-secretase-dependent gut-to-brain propagation of Abeta and Tau fibrils in Alzheimer's disease. EMBO JOURNAL. 2021, 40, e106320.

  1. Ahn, E. H.; Lei, K.; Kang, S. S.; Wang, Z. H.; Liu, X.; Hong, W.; Wang, Y. T.; Edgington-Mitchell, L. E.; Jin, L.; Ye, K. Mitochondrial dysfunction triggers the pathogenesis of Parkinson's disease in neuronal C/EBPbeta transgenic mice. MOLECULAR PSYCHIATRY. 2021, 26, 7838-7850.

  1. Kang, S. S.; Liu, X.; Ahn, E. H.; Xiang, J.; Manfredsson, F. P.; Yang, X.; Luo, H. R.; Liles, L. C.; Weinshenker, D.; Ye, K. Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus. JOURNAL OF CLINICAL INVESTIGATION. 2020, 130, 422-437.

  1. Wang, Z. H.; Xiang, J.; Liu, X.; Yu, S. P.; Manfredsson, F. P.; Sandoval, I. M.; Wu, S. X.; Wang, J. Z.; Ye, K. Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates delta-Secretase by Upregulating C/EBP beta in Alzheimer's Disease. CELL REPORTS. 2019, 28, 655-+.

  1. Wang, Z. H.; Gong, K.; Liu, X.; Zhang, Z. T.; Sun, X. O.; Wei, Z. Z.; Yu, S. P.; Manfredsson, F. P.; Sandoval, I. M.; Johnson, P. F.; Jia, J. P.; Wang, J. Z.; Ye, K. C/EBP beta regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease. NATURE COMMUNICATIONS. 2018, 9.

  1. Chen, C.; Wang, Z.; Zhang, Z.; Liu, X.; Kang, S. S.; Zhang, Y.; Ye, K. The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2018, 115, 578-583.

  1. Zhang, Z.; Obianyo, O.; Dall, E.; Du, Y.; Fu, H.; Liu, X.; Kang, S. S.; Song, M.; Yu, S. P.; Cabrele, C.; Schubert, M.; Li, X.; Wang, J. Z.; Brandstetter, H.; Ye, K. Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease. NATURE COMMUNICATIONS. 2017, 8, 14740.

  1. Zhang, Z.; Kang, S. S.; Liu, X.; Ahn, E. H.; Zhang, Z.; He, L.; Iuvone, P. M.; Duong, D. M.; Seyfried, N. T.; Benskey, M. J.; Manfredsson, F. P.; Jin, L.; Sun, Y. E.; Wang, J. Z.; Ye, K. Asparagine endopeptidase cleaves alpha-synuclein and mediates pathologic activities in Parkinson's disease. NATURE STRUCTURAL & MOLECULAR BIOLOGY. 2017, 24, 632-642.

  1. Wang, Z. H.; Liu, P.; Liu, X.; Manfredsson, F. P.; Sandoval, I. M.; Yu, S. P.; Wang, J. Z.; Ye, K. Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease. MOLECULAR CELL. 2017, 67, 812-825 e815.

  1. Zhang, Z.; Song, M.; Liu, X.; Su Kang, S.; Duong, D. M.; Seyfried, N. T.; Cao, X.; Cheng, L.; Sun, Y. E.; Ping Yu, S.; Jia, J.; Levey, A. I.; Ye, K. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease. NATURE COMMUNICATIONS. 2015, 6, 8762.

  1. Zhang, Z.; Song, M.; Liu, X.; Kang, S. S.; Kwon, I. S.; Duong, D. M.; Seyfried, N. T.; Hu, W. T.; Liu, Z.; Wang, J. Z.; Cheng, L.; Sun, Y. E.; Yu, S. P.; Levey, A. I.; Ye, K. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. NATURE MEDICINE. 2014, 20, 1254-1262.

  1. Jang, S. W.; Liu, X.; Yepes, M.; Shepherd, K. R.; Miller, G. W.; Liu, Y.; Wilson, W. D.; Xiao, G.; Blanchi, B.; Sun, Y. E.; Ye, K. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2010, 107, 2687-2692.

  1. Tang, X. L.; Jang, S. W.; Okada, M.; Chan, C. B.; Feng, Y.; Liu, Y.; Luo, S. W.; Hong, Y.; Rama, N.; Xiong, W. C.; Mehlen, P.; Ye, K. Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B. NATURE CELL BIOLOGY. 2008, 10, 698-706.

  1. Liu, Z.; Jang, S. W.; Liu, X.; Cheng, D.; Peng, J.; Yepes, M.; Li, X. J.; Matthews, S.; Watts, C.; Asano, M.; Hara-Nishimura, I.; Luo, H. R.; Ye, K. Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase. MOLECULAR CELL. 2008, 29, 665-678.

  1. Tang, X. L.; Jang, S. W.; Wang, X. R.; Liu, Z. X.; Bahr, S. M.; Sun, S. Y.; Brat, D.; Gutmann, D. H.; Ye, K. Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation. NATURE CELL BIOLOGY. 2007, 9, 1199-1207.

  1. Ahn, J. Y.; Liu, X.; Cheng, D.; Peng, J.; Chan, P. K.; Wade, P. A.; Ye, K. Nucleophosmin/B23, a nuclear PI(3,4,5)P(3) receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD. MOLECULAR CELL. 2005, 18, 435-445.

  1. Rong, R.; Tang, X. L.; Gutmann, D. H.; Ye, K. Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2004, 101, 18200-18205.

  1. Ahn, J. Y.; Rong, R.; Liu, X.; Ye, K. PIKE/nuclear PI 3-kinase signaling mediates the antiapoptotic actions of NGF in the nucleus. EMBO JOURNAL. 2004, 23, 3995-4006.

  1. Rong, R.; Ahn, J. Y.; Huang, H.; Nagata, E.; Kalman, D.; Kapp, J. A.; Tu, J.; Worley, P. F.; Snyder, S. H.; Ye, K. PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. NATURE NEUROSCIENCE. 2003, 6, 1153-1161.

  1. Ye, K.; Aghdasi, B.; Luo, H. B. R.; Moriarity, J. L.; Wu, F. Y.; Hong, J. J.; Hurt, K. J.; Bae, S. S.; Suh, P. G.; Snyder, S. H. Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE. NATURE. 2002, 415, 541-544.

  1. Ye, K.; Hurt, J.; Wu, F. Y.; Fang, M.; Luo, H. B. R.; Hong, J. J.; Blackshaw, S.; Ferris, C. D.; Snyder, S. H. PIKE: A nuclear GTPase that enhances PI3Kinase activity and is regulated by protein 4.1N. CELL. 2000, 103, 919-930.

  1. Ye, K.; Ke, Y.; Keshava, N.; Shanks, J.; Kapp, J. A.; Tekmal, R. R.; Petros, J.; Joshi, H. C. Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 1998, 95, 1601-1606.