Areas of Investigation

Research in our laboratory focuses on the biological and pathophysiological functions of apolipoprotein (apo) E. Long-term goals of our research are to understand the molecular and cellular mechanisms by which apoE4 increases the risk of Alzheimer’s disease (AD) and related neurodegeneratative disorders and to develop therapeutic strategies to treat or prevent AD.

Human apoE has three isoforms, apoE2, apoE3 and apoE4. ApoE4 is a major gene, with semi-dominant inheritance, for late-onset AD; however, its roles in the pathogenesis of AD are unclear.

We use neuronal cultures, induced pluripotent stem (iPS) cells and transgenic and gene-targeted mouse models to study the differential 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 AD and other apoE4-related neurodegenerative disorders.

Lab Focus

Validate the apoE proteolysis hypothesis of AD in animal models and humans.
Identify the protease responsible for apoE cleavage in neurons.
Determine how apoE4 fragments cause cytoskeletal disruption and mitochondrial dysfunction.
Develop therapeutic strategies targeting apoE4’s detrimental effects.
Determine the mechanisms controlling apoE expression in neurons.
Establish human iPS cell models of neurodegeneration.


Established the apoE proteolysis hypothesis of AD. This hypothesis suggests that, in response to stresses or injuries, neuronal apoE expression is triggered to facilitate neuronal repair. However, neuronal apoE undergoes proteolytic cleavage, with apoE4 being more susceptible to the cleavage than apoE3, resulting in the formation of neurotoxic fragments. The apoE4 fragments enter the cytosol and cause tau pathology and mitochondrial impairment, leading to neurodegeneration and learning and memory deficits.
Demonstrated that hilar GABAergic interneurons in the hippocampus are particularly vulnerable to apoE4 fragment toxicity and the resulting impairments contribute to learning and memory deficits.
Established human iPS cell models of AD and frontotemporal dementia.


  • American Heart Association
  • Society for Neuroscience
  • American Society for Biochemistry and Molecular Biology
  • Alzheimer’s Association
  • International Society to Advance Alzheimer’s Research and Treatment

Professional titles

Investigator, Roddenberry Center for Stem Cell Biology and Medicine at Gladstone;
Professor, Neurology and Pathology, University of California, San Francisco


  • Qingdao Medical University, Qingdao, China
  • Peking Union Medical College, Chinese Academy of Medical Sciences
  • Peking Union Medical College, Chinese Academy of Medical Sciences

Honors and Awards

2000 Young Investigator Award for Scientific Excellence, International Society for Atherosclerosis Research
1996 Young Investigator Award, XII International Symposium on Drugs Affecting Lipid Metabolism
1995 W.H. Hauss Award on Atherosclerosis Research, German Arteriosclerosis Research Society