YE Keqiang

YE Keqiang

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


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) Xiong, J.; Liao, J.; Liu, X.; Zhang, Z.; Adams, J.; Pacifici, R.; Ye, K. A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin. Nat Commun 2022, 13, 4820.

(2) 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, 603, 470-476.

(3) Xia, Y.; Qadota, H.; Wang, Z. H.; Liu, P.; Liu, X.; Ye, K. X.; Matheny, C. J.; Berglund, K.; Yu, S. P.; Drake, D.; Bennett, D. A.; Wang, X. C.; Yankner, B. A.; Benian, G. M.; Ye, K. Neuronal C/EBPbeta/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression. Sci Adv 2022, 8, eabj8658.

(4) 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. Prog Neurobiol 2022, 209, 102212.

(5) Liu, P.; Wang, Z. H.; Kang, S. S.; Liu, X.; Xia, Y.; Chan, C. B.; Ye, K. High-fat diet-induced diabetes couples to Alzheimer's disease through inflammation-activated C/EBPbeta/AEP pathway. Mol Psychiatry 2022, 19, 1283-1297.

(6) Kang, S. S.; Wu, Z.; Liu, X.; Edgington-Mitchell, L.; Ye, K. Treating Parkinson's Disease via Activation of BDNF/TrkB Signaling Pathways and Inhibition of Delta-Secretase. Neurotherapeutics 2022, Online ahead of print.

(7) Kang, S. S.; Meng, L.; Zhang, X.; Wu, Z.; Mancieri, A.; Xie, B.; Liu, X.; Weinshenker, D.; Peng, J.; Zhang, Z.; Ye, K. Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation. Nat Struct Mol Biol 2022, 29, 292-305.

(8) 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. Adv Sci (Weinh) 2022, 9, e2103396.

(9) 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, 71, 2233-2252.

(10) 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.

(11) 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. Mol Psychiatry 2021, 26, 2943-2963.

(12) 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 Neuropathol 2021, 142, 139-158.

(13) 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. Sci Adv 2021, 7.

(14) 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 J 2021, 40, e106320.

(15) 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. Mol Psychiatry 2021, 26, 7838-7850.

(16) 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. J Clin Invest 2020, 130, 422-437.

(17) 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 Rep 2019, 28, 655-+.

(18) 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. Nat Commun 2018, 9.

(19) 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. Proc Natl Acad Sci U S A 2018, 115, 578-583.

(20) 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. Nat Commun 2017, 8, 14740.

(21) 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. Nat Struct Mol Biol 2017, 24, 632-642.

(22) 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. Mol Cell 2017, 67, 812-825 e815.

(23) 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 commun 2015, 6, 8762.

(24) 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. Nat Med 2014, 20, 1254-1262.

(25) 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. Proc Natl Acad Sci U S A 2010, 107, 2687-2692.

(26) 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. Nat Cell Biol 2008, 10, 698-706.

(27) 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. Mol Cell 2008, 29, 665-678.

(28) 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. Nat Cell Biol 2007, 9, 1199-1207.

(29) 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. Mol Cell 2005, 18, 435-445.

(30) 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. Proc Natl Acad Sci U S A 2004, 101, 18200-18205.

(31) 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 J 2004, 23, 3995-4006.

(32) 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. Nat Neurosci 2003, 6, 1153-1161.

(33) 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.

(34) 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.

(35) 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. Proc Natl Acad Sci U S A 1998, 95, 1601-1606.