Research in my laboratory focuses on unraveling the molecular mechanisms of neurodegenerative diseases and identifying strategies for their treatment or prevention. Potential pathogenic factors are assessed in primary and stem cell-derived neural cultures in vitro and in genetically engineered mice in vivo. We are especially interested in apolipoprotein (apo) E4, the major known genetic risk factor for Alzheimer‛s disease (AD).
Studies from my laboratory have demonstrated that neuronal apoE is subject to cleavage, generating neurotoxic fragments. ApoE4 is more susceptible to cleavage than apoE3. When expressed in cultured neuronal cells the truncated apoE4 is neurotoxic, leading to cell death. Furthermore, expression of the truncated apoE4 causes AD-like neurodegeneration and behavioral deficits in transgenic mice.
- Harris FM, Walter JB, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, Fish JD, Masliah E, Hopkins PC, Scearce-Levie K, Weisgraber KH, Mucke L, Mahley RW, and Huang Y (2003). Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer‛s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl. Acad. Sci. USA. 100:10966-10971.
- Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q, Wyss-Coray T, Buttini M, Mucke L, Mahley RW, and Huang Y (2004) Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24:2527-2534.
- Chang S, Ma TR, Miranda RD, Balestra ME, Mahley RW, and Huang Y (2005) Lipid-and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc. Natl. Acad. Sci. USA. 102:18694-18699.
- Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, and Huang Y (2006) Profile and regulation of apolipoprotein (apo) E expression in central nervous system in mice with targeting of green fluorescent protein to the apoE locus. J. Neurosci. 26:4985-4994.
- Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, Halabisky B, Deng C, Mahley RW, and Huang Y (2009) GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knock-in mice. Cell Stem Cell. 5:634–645.
- Boehringer-Ingelheim Postdoctoral Fellowship Award in Biomedical Research.
- W. H. Hauss Award on Arteriosclerosis Research, German Arteriosclerosis Research Society.
- Young Investigator Award, XII International Symposium on Drugs Affecting Lipid Metabolism, International Society for Arteriosclerosis Research, Houston, TX.
- Young Investigator Award, International Society for Arteriosclerosis Research, Stockholm, Sweden