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 Karl H. Weisgraber, Ph.D.
Senior Investigator
Gladstone Institute of Neurological Disease
Professor of Pathology
University of California, San Francisco
Email: kweisgraber@gladstone.ucsf.edu
Telephone: 415-734-2000
Fax: 415-355-0824
Areas of Investigation
Our research seeks to understand the mechanisms underlying the association of apoE4 with Alzheimer's disease and to develop therapeutic approaches to reduce the apoE4 impact.
Significance
ApoE plays a key role in transporting lipids in the blood and brain. ApoE4 is a major risk factor for Alzheimer’s disease and is associated with an increased risk for heart disease. It is also associated with poor clinical outcome in patients with acute head trauma. Defining the effects of the three apoE isoforms and how they function in plasma and the brain should provide crucial insights into the impact of apoE4 on neurological disease and atherosclerosis.
Approaches
Our central hypothesis is that one or more of the structural and biophysical differences among the isoforms play a major role in the association of apoE with disease. |
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| We identified three distinguishing characteristics of apoE4: 1) apoE4 domain interaction, 2) apoE4 forms a molten globule, and 3) apoE4 lacks cysteine. Our experimental approach is to translate our structural and biophysical findings into mouse models by genetically altering the mouse Apoe gene to humanize it with respect to each of the human isoform differences. We use physical-chemical techniques, including x-ray crystallography, in combination with site-directed mutagenesis to probe apoE-related structure and function questions. Our research focuses on understanding the effect of apoE structure on metabolism and disease with the potential of discovering new potential therapeutic targets. |
Previous Accomplishments
- Determined the structural differences among the apoE isoforms.
- Described the domain structure of apoE and functional regions of the protein.
- Discovered apoE4 domain interaction.
- Generated a mouse model specific for domain interaction.
- Established that domain interaction contributes functional and cognitive deficits
- Established that domain interaction is a viable therapeutic target.
- Established proof of principle that small molecules can correct apoE4 domain interaction.
Areas for Future Direction - Determine the structural and biophysical differences among the apoE isoforms that underlie the association of apoE4 with disease.
- Determine the isoform-specific role of apoE in the progression and regression of atherosclerosis.
- Determine the structural changes that occur in apoE with lipid association.
Selected References
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