DavidKang

David Kang, PhD

Assoc Professor, College Of Medicine Molecular Medicine

College Of Medicine Molecular Medicine

Contact Info 4001 E. Fletcher Ave - MDC36
Tampa, FL 33613

Academic Email: dkang@health.usf.edu

Education

  • PhD, Neurosciences, University Of California, San Diego, 1999
  • PhD, Neurosciences, University of California, San Diego, 1999
  • BA, Natural Science / Psychology, Illinois Wesleyan University, 1993

Interdisciplinary and Emerging Signature Programs

  • Neuroscience

Research Interests

  • My research focuses on the mechanisms of neurodegeneration in Alzheimer’s disease (AD) and related neurological disorders. AD is the leading cause of dementia and most prevalent neurodegenerative disease, affecting more than 40 million people worldwide. Pathologically, brains afflicted with AD are riddled with accumulations of two highly toxic proteins, namely amyloid beta and tau, which are the underlying cause of neurodegeneration. The amyloid beta protein is derived from 2 proteolytic cuts made in its precursor protein, APP, and it is widely believed that Abeta induces early neurogeneration and promotes pathology associated with the tau protein.
  • In my lab, we utilize various molecular, biochemical, cell biological, and animal modeling tools to answer important questions pertinent to healthy and pathological neuronal function. Some of these tools include confocal microscopy, fluorescence live cell imaging, calcium imaging, axonal transport of cargo proteins & organelles, generation & use of transgenic and knockout models, in vivo neurogenesis / neuronal migration assays, cell death assays, and membrane protein trafficking assays, etc. Broad questions directly relevant to our ongoing studies are the following. 1) What are the molecular pathways and therapeutic targets of Abeta generation? 2) What are the molecular pathways and therapeutic targets of Abeta-induced neurotoxicity? 3) How do Abeta-neurotoxic pathways induce synaptic damage, mitochondrial dysfunction, and tau pathology? 4) What are some naturally protective mechanisms and pathways against neurodegeneration?
  • My earlier work originally identified the genetic association of LRP, an apoE receptor, to late-onset AD. Later work by us and others found that LRP plays a dual and opposing role in APP metabolism: 1) sequestration and removal of secreted amyloid beta protein and 2) promotion of Abeta generation by increasing APP processing. We recently found that LRP is required for the majority of Abeta generation by promoting the trafficking APP to lipid rafts, cholesterol-rich intracellular microdomains highly enriched in Abeta generating proteases. We narrowed the Abeta promoting region of LRP to the C-terminal 37 residues. Using a yeast 2-hybrid screen, we identified several new proteins, which interact with the C-terminal 37 residues of LRP cytoplasmic tail (C37). One such C37 interacting protein was Ran-Binding Protein 9 (RanBP9), a multimodular scaffolding protein. We found that LRP and APP interact with each other on the neuronal surface, and RanBP9 helps to stabilize this interaction, which accelerates their internalization from the cell surface. Such endocytic event is critical for the generation of Abeta, and RanBP9 levels are highly increased in brains of AD patients and animal models of AD. We have also found that RanBP9 interacts with and helps to internalize integrins from the cell surface, thereby disrupting cell adhesions while simultaneously increasing Abeta production. On the other hand, integrins are critical for transmitting the toxic Abeta signals from the cell surface through a series of events (i.e. disruption of focal adhesions) that require RanBP9 and a downstream apoptotic / actin-binding protein, cofilin, eventually leading to the disruption of cell/synaptic integrity and mitochondrial function. Our working hypothesis based on experimental findings is that cell surface receptors and their intracellular pathways that promote the generation of Abeta are largely identical to the very pathways that transmit the neurotoxic signals induced by Abeta (i.e. integrins / LRP / APP / RanBP9 / Cofilin, etc.). In collaboration with Drs. Uversky and Chen in our department, we are also using biophysical and computational tools to structurally define various molecular targets for rational drug design in addition to the screening of compound libraries for AD therapeutics.

Recent Publications

  • Lakshmana, MK.Hayes, CD.Bennett, SP.Bianchi, E.Reddy, KM.Koo, EH.Kang, DE. Role of RanBP9 on amyloidogenic processing of APP and synaptic protein levels in the mouse brain. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 26(5) : 2072-83, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22294787
  • Woo, JA.Roh, SE.Lakshmana, MK.Kang, DE. Pivotal role of RanBP9 in integrin-dependent focal adhesion signaling and assembly. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 26(4) : 1672-81, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22223749
  • Shilling, D.Mak, DO.Kang, DE.Foskett, JK. Lack of evidence for presenilins as endoplasmic reticulum Ca2+ leak channels. The Journal of biological chemistry. , 2012. http://www.ncbi.nlm.nih.gov/pubmed/22311977
  • Woo, JA.Jung, AR.Lakshmana, MK.Bedrossian, A.Lim, Y.Bu, JH.Park, SA.Koo, EH.Mook-Jung, I.Kang, DE. Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration. Cell death and differentiation. , 2012. http://www.ncbi.nlm.nih.gov/pubmed/22361682
  • Kang, DE.Roh, SE.Woo, JA.Liu, T.Bu, JH.Jung, AR.Lim, Y. The Interface between Cytoskeletal Aberrations and Mitochondrial Dysfunction in Alzheimer's Disease and Related Disorders. Experimental neurobiology. 20(2) : 67-80, 2011. http://www.ncbi.nlm.nih.gov/pubmed/22110363
  • Lakshmana, MK.Chung, JY.Wickramarachchi, S.Tak, E.Bianchi, E.Koo, EH.Kang, DE. A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid-beta peptide generation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 24(1) : 119-27, 2010. http://www.ncbi.nlm.nih.gov/pubmed/19729516
  • Cheung, KH.Mei, L.Mak, DO.Hayashi, I.Iwatsubo, T.Kang, DE.Foskett, JK. Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. Science signaling. 3(114) : ra22, 2010. http://www.ncbi.nlm.nih.gov/pubmed/20332427
  • Lakshmana, MK.Yoon, IS.Chen, E.Bianchi, E.Koo, EH.Kang, DE. Novel role of RanBP9 in BACE1 processing of amyloid precursor protein and amyloid beta peptide generation. The Journal of biological chemistry. 284(18) : 11863-72, 2009. http://www.ncbi.nlm.nih.gov/pubmed/19251705
  • Boo, JH.Song, H.Kim, JE.Kang, DE.Mook-Jung, I. Accumulation of phosphorylated beta-catenin enhances ROS-induced cell death in presenilin-deficient cells. PloS one. 4(1) : e4172, 2009. http://www.ncbi.nlm.nih.gov/pubmed/19137062
  • Lakshmana, MK.Chen, E.Yoon, IS.Kang, DE. C-terminal 37 residues of LRP promote the amyloidogenic processing of APP independent of FE65. Journal of cellular and molecular medicine. 12(6B) : 2665-74, 2008. http://www.ncbi.nlm.nih.gov/pubmed/18373737
  • Yoon, IS.Chen, E.Busse, T.Repetto, E.Lakshmana, MK.Koo, EH.Kang, DE. Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 21(11) : 2742-52, 2007. http://www.ncbi.nlm.nih.gov/pubmed/17463224
  • Kang, DE.Yoon, IS.Repetto, E.Busse, T.Yermian, N.Ie, L.Koo, EH. Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. The Journal of biological chemistry. 280(36) : 31537-47, 2005. http://www.ncbi.nlm.nih.gov/pubmed/16014629
  • Yoon, IS.Pietrzik, CU.Kang, DE.Koo, EH. Sequences from the low density lipoprotein receptor-related protein (LRP) cytoplasmic domain enhance amyloid beta protein production via the beta-secretase pathway without altering amyloid precursor protein/LRP nuclear signaling. The Journal of biological chemistry. 280(20) : 20140-7, 2005. http://www.ncbi.nlm.nih.gov/pubmed/15772078
  • Chevallier, NL.Soriano, S.Kang, DE.Masliah, E.Hu, G.Koo, EH. Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation. The American journal of pathology. 167(1) : 151-9, 2005. http://www.ncbi.nlm.nih.gov/pubmed/15972961
  • Kang, DE.Soriano, S.Xia, X.Eberhart, CG.De Strooper, B.Zheng, H.Koo, EH. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 110(6) : 751-62, 2002. http://www.ncbi.nlm.nih.gov/pubmed/12297048
  • Weggen, S.Eriksen, JL.Das, P.Sagi, SA.Wang, R.Pietrzik, CU.Findlay, KA.Smith, TE.Murphy, MP.Bulter, T.Kang, DE.Marquez-Sterling, N.Golde, TE.Koo, EH. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 414(6860) : 212-6, 2001. http://www.ncbi.nlm.nih.gov/pubmed/11700559
  • Soriano, S.Kang, DE.Fu, M.Pestell, R.Chevallier, N.Zheng, H.Koo, EH. Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. The Journal of cell biology. 152(4) : 785-94, 2001. http://www.ncbi.nlm.nih.gov/pubmed/11266469
  • Kang, DE.Pietrzik, CU.Baum, L.Chevallier, N.Merriam, DE.Kounnas, MZ.Wagner, SL.Troncoso, JC.Kawas, CH.Katzman, R.Koo, EH. Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway. The Journal of clinical investigation. 106(9) : 1159-66, 2000. http://www.ncbi.nlm.nih.gov/pubmed/11067868
  • Van Uden, E.Kang, DE.Koo, EH.Masliah, E. LDL receptor-related protein (LRP) in Alzheimer's disease: towards a unified theory of pathogenesis. Microscopy research and technique. 50(4) : 268-72, 2000. http://www.ncbi.nlm.nih.gov/pubmed/10936878
  • Kang, DE.Soriano, S.Frosch, MP.Collins, T.Naruse, S.Sisodia, SS.Leibowitz, G.Levine, F.Koo, EH. Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential activity of Alzheimer's disease-linked PS1 mutants in the beta-catenin-signaling pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience. 19(11) : 4229-37, 1999. http://www.ncbi.nlm.nih.gov/pubmed/10341227
  • Katzman, R.Kang, D.Thomas, R. Interaction of apolipoprotein E epsilon 4 with other genetic and non-genetic risk factors in late onset Alzheimer disease: problems facing the investigator. Neurochemical research. 23(3) : 369-76, 1998. http://www.ncbi.nlm.nih.gov/pubmed/9482249
  • Tanaka, S.Chen, X.Xia, Y.Kang, DE.Matoh, N.Sundsmo, M.Thomas, RG.Katzman, R.Thal, LJ.Trojanowski, JQ.Saitoh, T.Ueda, K.Masliah, E. Association of CYP2D microsatellite polymorphism with Lewy body variant of Alzheimer's disease. Neurology. 50(6) : 1556-62, 1998. http://www.ncbi.nlm.nih.gov/pubmed/9633694
  • Zhang, J.Kang, DE.Xia, W.Okochi, M.Mori, H.Selkoe, DJ.Koo, EH. Subcellular distribution and turnover of presenilins in transfected cells. The Journal of biological chemistry. 273(20) : 12436-42, 1998. http://www.ncbi.nlm.nih.gov/pubmed/9575200
  • Komori, N.Kittel, A.Kang, D.Shackelford, D.Masliah, E.Zivin, JA.Saitoh, T. Reversible ischemia increases levels of Alzheimer amyloid protein precursor without increasing levels of mRNA in the rabbit spinal cord. Brain research. Molecular brain research. 49(1-2) : 103-12, 1997. http://www.ncbi.nlm.nih.gov/pubmed/9387869
  • Saitoh, T.Kang, D.Mallory, M.DeTeresa, R.Masliah, E. Glial cells in Alzheimer's disease: preferential effect of APOE risk on scattered microglia. Gerontology. 43(1-2) : 109-18, 1997. http://www.ncbi.nlm.nih.gov/pubmed/8996833
  • Kang, DE.Saitoh, T.Chen, X.Xia, Y.Masliah, E.Hansen, LA.Thomas, RG.Thal, LJ.Katzman, R. Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease. Neurology. 49(1) : 56-61, 1997. http://www.ncbi.nlm.nih.gov/pubmed/9222170
  • Conrad, C.Andreadis, A.Trojanowski, JQ.Dickson, DW.Kang, D.Chen, X.Wiederholt, W.Hansen, L.Masliah, E.Thal, LJ.Katzman, R.Xia, Y.Saitoh, T. Genetic evidence for the involvement of tau in progressive supranuclear palsy. Annals of neurology. 41(2) : 277-81, 1997. http://www.ncbi.nlm.nih.gov/pubmed/9029080
  • Yoshimoto, M.Iwai, A.Kang, D.Otero, DA.Xia, Y.Saitoh, T. NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proceedings of the National Academy of Sciences of the United States of America. 92(20) : 9141-5, 1995. http://www.ncbi.nlm.nih.gov/pubmed/7568089
  • Dornan, WA.Kang, DE.McCampbell, A.Kang, EE. Bilateral injections of beta A(25-35) + IBO into the hippocampus disrupts acquisition of spatial learning in the rat. Neuroreport. 5(2) : 165-8, 1993. http://www.ncbi.nlm.nih.gov/pubmed/8111004

Positions Held

  • Associate Professor (Dept. of Neurosciences, University of California, San Diego 2010 - 2012)
  • Assistant Professor (Dept. of Neurosciences, University of California, San Diego 2004 - 2010)