Robert W. Mahley
The J. David Gladstone Institutes
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Primary Section: 42, Medical Physiology and Metabolism Secondary Section: 41, Medical Genetics, Hematology, and Oncology Membership Type:
Member
(elected 2000)
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Research Interests
For 40+ years I have continued to focus on understanding the structure and function of apoE in cardiovascular and neurological diseases. 1. Exploration of the role of apoE in neurobiology and Alzheimer's disease 2. Unique structure of apoE4 (domain interaction) triggers in vitro and in vivo neuropathologic changes. Small molecules that disrupt domain interaction have been identified, converting apoE4 to an apoE3 or apoE2 structure and blocking the detrimental effects of apoE4, including apoE4-associated mitochondrial dysfunction, impaired neurite outgrowth, impaired mitochondrial motility, and generation of neurotoxic fragments. 3. Generation of apoE neurotoxic fragments in neurons causes apoE4-associated neuropathology. When neurons are injured or stressed, they turn on the synthesis of apoE. In the context of apoE4, neuropathology results because apoE4 undergoes neuron-specific proteolysis, generating neurotoxic fragments. The mechanism whereby the fragments are generated, escape the secretory pathway, and enter the cytosol has been defined. 4. Determination of the structure and function of the apoE isoforms. The three-dimensional structure of the amino-terminal two-thirds of apoE3 and apoE2 defined the structure of the LDL receptor binding region and established the mechanisms whereby apoE2 showed defective receptor binding. 5. Identification of the role of apoE in cholesterol metabolism and cardiovascular disease.
