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 relationship of the structure and function of apolipoprotein (apo) E in cardiovascular and Alzheimer’s disease. The three common isoforms of apoE, apoE2, apoE3, and apoE4 differ in structure leading to very different metabolic properties with a dramatic impact on disease.
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. 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 of apoE4 domain interaction.
Established that apoE4 is the least stable isoform and forms a molten globule state.
Generated a hypomorphic apoE mouse model to study the progression and regression of atherosclerosis.
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.
Karl H. Weisgraber, Ph.D.