Shi Du Yan, M.D. Shi Du Yan, M.D.
Professor, Clinical Pathology
 Email: sdy1@columbia.edu
Tel: (212) 342-1304

Research in my laboratory focuses on investigating the cellular and molecular mechanisms of cellular stress and survival in neurodegenerative disorders relevant to Alzheimer’s disease (AD) and Parkinson disease.  We have first identified the specific cellular targets (RAGE, receptor for advanced glycation end product; and ABAD, amyloid binding alcohol dehydrogenase) of amyloid-beta peptide (Aβ) and provided the evidence of Aβ-mediated neuronal stress. We developed a novel transgenic mouse model relevant to AD and tested the role of RAGE and ABAD in Aβ-mediated cellular perturbation in those AD type mouse models. Dr. Yan and her research team are the major group investigating these paradigms. Mitochondrial dysfunction is a hallmark of AD. We have discovered that Aβ progressively accumulated in mitochondria of brains from AD patients and transgenic AD-type mouse model. Accumulation of Aβ in mitochondria was associated with mitochondrial dysfunction. ABAD directly linked to mitochondrial toxicity induced by Aβ. These studies provide new insights into mechanisms of Aβ-mediated mitochondrial toxicity causing neuronal damage relevant to AD and open new avenue for treatment of AD. We are identifying proteins which interact with mitochondrial Aβ in transgenic AD-type mouse models implicating for pathogenesis of Alzheimer’s disease. In addition, we are focusing on cellular and molecular mechanisms underlying ischemia-induced cardiac and cerebral injury, and autoimmune disease such as EAE (experimental autoimmune encephalomyelitis) animal model relevant to multiple sclerosis.

 

Selected Recent Publications:

  • Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang, N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SD, Wu H. (2004) ABAD Directly Links Aß to Mitochondrial Toxicity in Alzheimer's Disease.  Science 2004 304: 448-452 (co-corresponding author). Faculty of 1000 Top 10 Neuroscience.

  • Yan SS, Wu ZY, Zhang HP, Furtado G, Chen X, Yan SF, Schmidt AM, Brown C, Stern A, LaFaille J, Chess L, Stern DM, Jiang H. Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system. Nature Medicine. 2003 Mar; 9(3): 287- 93. Epub 2003 Feb 24. (C

  • Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A, Yan SF, Stern A, Luddy JS, Lue LF, Walker DG, Roher A, Buttini M, Mucke L, Li W, Schmidt AM, Kindy M, Hyslop PA, Stern DM, Yan SS. RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J. 2004 Sep 30:1-10. Faculty of 1000 Top 10 Neuroscience.

  • Takuma K, Yao J, Huang J, Xu H, Chen X, Luddy J, Trillat AC, Stern DM, Arancio O, Yan SS. ABAD.  enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J. 2005 Apr;19(6):597-8. Epub 2005 Jan 21.

  • Yan SD, Stern DM. Mitochondrial dysfunction and Alzheimer's disease: role of amyloid-beta peptide alcohol dehydrogenase (ABAD).  Int J Exp Pathol. 2005 Jun; 86(3): 161-71. (Corresponding author). (One of the top ten most cited  papers from 2005)

  • Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan. SD. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005 Dec;19(14):2040-1. Epub 2005 Oct 6.

  • Xie Y, Deng S, Chen Z, Yan SD, Landry DW. Identification of small-molecule inhibitors of the Abeta-ABAD interaction. Bioorg Med Chem Lett. 2006 Sep 1;16(17):4657-60. Epub 2006 Jun 14.

  • Yan Y, Liu Y, Sorci M, Belfort G, Lustbader JW, Yan SD, Wang C. Surface Plasmon Resonance and Nuclear Magnetic Resonance Studies of ABAD-Abeta Interaction. Biochemistry. 2007 Jan 25.

  • Yao J, Taylor M, Davey F, Ren Y, Aiton J, Coote P, Fang F, Chen JX, Yan SD, Gunn-Moore FJ. Interaction of amyloid binding alcohol dehydrogenase/Abeta mediates up-regulation of peroxiredoxin II in the brains of Alzheimer’s disease patients and a transgenic Alzheimer’s disease mouse model. Mole Cell Neurosci. 2007 June: 35(2):377-82. Epub 2007 Apr 1.

  • Chen JX and Yan SD. Amyloid-beta-induced mitochondrial dysfunction. J Alzheimer’s Disease. 2007  Sep: 12(2):177-84.

  • Chen JX and Yan SD. Pathogenic role of mitochondrial amyloid- peptide. Exp Rev Neurother November 2007, Vol. 7, No. 11, Pages 1499-1516

  • Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF, Yan SD. RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer's disease. Curr Mol Med. 2007 Dec;7(8):735-42.

  • Chen X, Stern D, and Yan SD. Cellular targets of amyloid beta peptide: potential roles in neuronal cell stress and toxicity. Chapter 11, Neurobiology of Alzheimer’s disease (Molecular and cellular biology series), third  edition, Oxford publication, 2007. p227-244.

  • Ren Y, Xu HW, Davey F, Taylor M, Aiton J, Coote P, Fang F, Yao J, Chen JX, Yan SD, Gunn-Moore FJ.  Endophilin I expression is increased in the brains of Alzheimer's disease patients. J Biol Chem. 2008 Feb 29; 283(9):5685-91. Epub 2007 Dec 31.

  • Origlia N, Righi M, Capsoni S, Cattaneo A, Fang F, Stern DM,  Chen JX,  Schmidt AM, Arancio O, Yan SD,  Domenici L. Receptor for Advanced Glycation Endproducts (RAGE)-dependent activation of p38 Mitogen-Activated Protein Kinase contributes to amyloid β-mediated cortical synaptic dysfunction. J. Neurosci. 2008 Mar 26;28:3521-3530.

  • Fukuzaki E, Takuma K, Funatsu Y, Himeno Y, Kitahara Y, Gu B, Mizoguchi H, IbiD, Koike K, Inoue M, Yan SD, Yamada K. Ovariectomy increases neuronal amyloid-beta binding alcohol dehydrogenase level in the mouse hippocampus. (co-corresponding author)Neurochem Int. 2008 Mar 10; [Epub ahead of print]