Unraveling ApoE4 Promotion of Cardiometabolic Disease

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Project Summary/Abstract The greatest genetic risk factor for late-onset Alzheimer’s disease (AD) is the ε4 allele of apolipoprotein E (apoE), or apoE4. In work in our parent R01 project entitled “Unraveling ApoE4 Promotion of Cardiometabolic Disease” we have discovered in mice that apoE4 actions via the apoE receptor apoER2 in endothelial cells attenuate endothelial insulin transport to the skeletal muscle to cause peripheral insulin resistance. We have also discovered that apoE4 is prothrombotic, most likely also through processes mediated by endothelial apoER2. We are in the process of testing if genetic correction of apoE4 to apoE3 in the liver by base editing reverses the negative impact of apoE4 on peripheral insulin resistance and thrombosis. The newly-discovered adverse effects of apoE4 on endothelial insulin transport and thrombosis may be critically involved in the detrimental impact of apoE4 on AD. Therefore, in the administrative supplement project we propose to determine if via endothelial apoER2, apoE4 impairs CNS insulin delivery and action and promotes CNS microvascular thrombosis. We also propose to determine if base editing of apoE4 to apoE3 in the liver prevents the adverse effects of apoE4 in the CNS. Doing so will determine how liver-derived apoE4 impacts processes in the CNS, and also provide a potential means to prevent adverse processes in the CNS caused by apoE4 without requiring intervention within the CNS. Positive results in the administrative supplement project will lead to a new and unique future R01 project in which we determine in a mouse model of AD how the revealed mechanisms contribute to the adverse impact of apoE4 on AD pathologic features and AD-related impairment in cognitive function. In the future project we will additionally determine if base editing of apoE4 to apoE3 in the liver reverses the detrimental effects of apoE4 on AD. Thus, springboarding from recent discoveries in our parent R01 project, the administrative supplement project will allow us to leverage our expertise in endothelial cell biology to gain new insights about apoE4 actions relevant to AD and possible means to negate them.