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 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), a devastating, incurable disorder whose cause is unknown.
We showed that apoE4 is cleaved into toxic fragments that may represent a major early event in AD pathology. A neuron-specific, chymotrypsin-like serine protease generates bioactive carboxyl-terminal-truncated fragments of apoE. Similar fragments are found in the brains of AD patients, where they form, together with the phosphorylated tau, one of the hallmark lesions of the disease-neurofibrillary tangles within neurons. ApoE4 is more susceptible to cleavage than the two other isoforms of apoE, which are not associated with increased risk of AD. When expressed in cultured neuronal cells, truncated apoE4 is neurotoxic, leading to cell death. When expressed in transgenic mice, it causes AD-like neurodegeneration and behavioral deficits. Thus, the apoE-cleaving enzyme represents a new therapeutic target for AD drug development.
Since the pathogenesis of neurodegenerative diseases is multifactorial, we use a variety of techniques in our research, including molecular and cellular biology, generation and characterization of transgenic and gene-targeted mouse models, neuropathology and neuropharmacology, imaging techniques, and proteomics.
In ongoing studies, we are investigating how apoE expression is regulated in neurons, the mechanisms underlying apoE4's susceptibility to proteolysis, and how apoE4 and its fragments cause neuronal and cognitive deficits. We are also seeking to identify and characterize the apoE-cleaving enzyme, with the goal of identifying its inhibitors and testing them in our animal models and, ultimately, in AD patients. |
Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW (2001) Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc. Natl. Acad. Sci. USA. 98:8838-8843.
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.
Harris FM, Tesseur T, Brecht WJ, Xu Q, Mullendorff K, Chang S, Wyss-Coray T, Mahley RW, and Huang Y (2004) Astroglial regulation of apolipoprotein E expression in neuronal cells: Implications for Alzheimer's disease. J. Biol. Chem. 279:3862-3868.
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.
Xu Q, Brecht WJ, Weisgraber KH, Mahley RW, and Huang Y (2004) Apolipoprotein E4 domain interaction occurs in living neuronal cells as determined by fluorescence resonance energy transfer. J. Biol. Chem . 279:25511-25516.
Harris FM, Brecht WJ, Xu Q, Mahley RW, and Huang Y (2004) Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: Modulation by Zinc. J. Biol. Chem. 279:44795-44801.
Huang Y, Weisgraber KH, Mucke L, and Mahley RW (2004) Apolipoprotein E: Diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease. J. Mol. Neurosci. 23:187-202.
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.
information last updated June 2006
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Biomedical Sciences (BMS) Graduate Program
