Yadong Huang, M.D., Ph.D.
Assistant Investigator Gladstone Institute of Neurological Disease Assistant Professor of Pathology and Neurology
University of California, San Francisco
Email: yhuang@gladstone.ucsf.edu Telephone: 415-734-2000
Fax: 415-355-0824
Areas of Investigation
Research in our laboratory focuses on the biological and pathophysiological functions of apolipoprotein (apo)E. A long-term goal of our research is to understand the molecular and cellular mechanisms by which apoE4 increases the risk of Alzheimer’s disease (AD) and related neurodegeneratative disorders.
Significance
Human apoE has three major isoforms, apoE2, apoE3, and apoE4. ApoE4 has been linked to the pathogenesis of AD. ApoE is found in both neuritic amyloid plaques and neurofibrillary tangles - the neuropathological hallmarks of AD - but its role in the pathogenesis of these two lesions is unclear.
Approaches
We use neuronal cultures and transgenic and gene-targeted mouse models to study the different effects of apoE3 and apoE4 on cell signaling pathways and cytoskelatal structure and function at molecular, cellular, and behavioral levels. We also use these approaches to develop and evaluate novel treatment strategies for apoE4-related neurodegenerative disorders.
Contributions
During past years, we investigated the interactions of apoE3 and apoE4 with cytoskeletal components and mitochondria and their potential roles in the formation of neurofibrillary tangles and mitochondrial dysfunction. We hypothesized that endogenously synthesized apoE isoforms interact differentially with (or modulate) the cytoskeleton and mitochondria, contributing to neurofibrillary tangle formation and mitochondrial dysfunction. Our results demonstrated that the carboxyl-terminal-truncated forms of apoE enter the cytosol and interact with the cytoskeletal components and mitochondria, resulting in the formation of neurofibrillary tangle-like structures and mitochondrial dysfunction in neurons.
Some Questions Addressed in Ongoing Studies:
Why is apoE4 more susceptible than apoE3 to proteolysis?
Which enzyme or enzymes are responsible for apoE cleavage?
How do apoE4 fragments cause cytoskeletal disruption and mitochondrial dysfunction?
Can we protect mice or humans from apoE4-related neurodegeneration by blocking its proteolysis?
Yadong Huang, M.D., Ph.D.