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2014 Grants - Kanekiyo
ApoE and LRP1 in Neuronal ABeta Clearance
Takahisa Kanekiyo, M.D., Ph.D.
Mayo Clinic Jacksonville
2014 New Investigator Research Grant
ABeta (also known as beta-amyloid) is a protein fragment thought to play an important role in the development of Alzheimer’s disease. In the brain, beta-amyloid can form clumps known as amyloid plaques, which are one of the characteristic features of Alzheimer’s disease.
The strongest genetic risk factor for late-onset Alzheimer’s disease is the epsilon-4 variant of the apolipoprotein E gene (APOE-ɛ4). People carrying the APOE-ɛ4 gene are more likely to develop amyloid plaques in the brain. The protein coded by the APOE gene helps in the breakdown and clearance of beta-amyloid in the brain, but evidence suggests that the ɛ4 version may be less effective at beta-amyloid clearance than other naturally occurring versions.
Takahisa Kanekiyo, M.D., Ph.D., and colleagues have proposed a series of studies to explore how different versions of the ApoE protein affect the clearance of beta-amyloid from the brain. Part of this function involves interaction with another protein known as LRP1 (low-density lipoprotein receptor-related protein1). The research team will first use nerve cells grown in laboratory dishes to study the how the interaction of different versions of ApoE with LRP1 affects beta-amyloid clearance. They will then follow those cell-specific experiments with studies in mice genetically altered to have an Alzheimer’s-like condition, and engineered to have different versions of ApoE and different levels of the LRP1 protein. They will explore how these differences affect the development of amyloid plaques in the brain. These studies will provide new insights into the possible mechanisms by which some versions of the APOE gene increase the risk of Alzheimer’s disease, and may suggest targets for the development of novel therapies.