Mayo Clinic discovery scientists are working to better understand the pathology of Alzheimer's, and are one step closer with research on a gene variant that reduces the risk of Alzheimer's disease and dementias published in Science Translational Medicine.
The apolipoprotein E, or APOE, gene is the strongest genetic risk factor for developing Alzheimer's disease. However, a rare variant of this gene that was previously identified by Mayo researchers as APOE p. V236E, is associated with a protective effect. The gene variant is now named after the city where the research team is based: APOE3-Jacksonville, or APOE3-Jac for Jacksonville, Florida. To understand the mechanisms that underlie that protective effect, the researchers performed genetic testing and pathological analysis using donated postmortem brain tissue samples from the Mayo Clinic Brain Bank for their study.
The APOE gene makes a protein ― also called APOE ― that helps cells harvest particles containing fat and protein. An example of these particles, called lipoproteins, is HDL or "good" cholesterol. But when APOE becomes dysfunctional, it affects the way another protein, called amyloid beta, comes together and clumps. Those protein clots, called amyloid plaques, together with neurofibrillary tangles, lead to inflammation and neurotoxicity, which are a hallmark of Alzheimer's disease.
The researchers analyzed the beta amyloid plaques and protein tangles in donated brain tissue and performed biochemical tests in cellular and animal models. They demonstrated that the protective benefit of APOE3-Jac was due to its ability to reduce APOE clumping and increase the formation of lipid particles important for the function of nerve cells. The researchers found that mice expressing the APOE3-Jac gene mutation in the study had less plaque buildup in the brain and reduced neuronal damage. They found that brain tissue in these mice contained more cholesterol and lipids ― key to memory formation and reducing Alzheimer pathology. This may explain the beneficial effect of the gene mutation.
"Our findings suggest that compounds targeting APOE clumping might reproduce the protective effects of the APOE3-Jac variant and should be explored as a therapeutic intervention strategy for neurodegeneration," says Guojun Bu, Ph.D., a Mayo Clinic molecular neuroscientist and senior author. "This gene variant has a functional advantage over other more common forms of the APOE gene." Dr. Bu is the Mary Lowell Leary Professor of Medicine and chair of the Department of Neuroscience at Mayo Clinic in Florida. He is also the associate director of Mayo Clinic's Alzheimer's Disease Research Center.
This study was supported in part by National Institutes of Health grants and the Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program. See the paper for a full list of funding sources, authors and competing interest disclosures.