Abca1 Regulates Lipid Metabolism and Tau Pathology in P301S/ApoE4 Mice

The goal of the project is to decipher if the overexpression of Abca1 in glia would exert neuroprotection and decrease tau pathology in the P301S/ApoE4 mouse model of tauopathy and Alzheimer’s disease.

ApoE4 is the strongest genetic risk factor for developing late-onset AD and was shown to markedly elevate tau pathology and neurodegeneration in the P301S/ApoE4 tauopathy mice. A disruption of lipid metabolism in glia is linked to neuroinflammation and neurodegeneration in several studies; we recently detected a significant buildup of lipids in glia of aged P301S/ApoE4 animals. In this study, we will assess the role of Abca1 lipid transporter in modulation of glial lipid metabolism in the P301S/ApoE4 mice, thus, providing novel therapeutic avenues for treating tauopathy and AD.

To date, it is unknown whether lipid accumulation in glia plays a significant role in ApoE4- and tau-mediated neurodegeneration and Alzheimer’s disease. This project is innovative because, for the first time, it addresses the role of cholesterol efflux transporter Abca1 in the regulation of glial cell metabolism, neuroinflammation, neurodegeneration in vivo, and lipid handling and tau-mediated toxicity in vitro. Together, these studies may demonstrate whether increasing lipid efflux in glia by targeting Abca1 could serve as a viable strategy to reduce tau pathology and neurodegeneration.

Once complete, this project should demonstrate whether increasing cholesterol efflux in glia by overexpressing the Abca1 lipid transporter could serve as a novel therapeutic strategy to mitigate tau pathology and associated neurodegeneration in vivo. These results could indicate that targeting glial lipid metabolism, primarily via modulation of expression of the late-onset Alzheimer’s disease genetic risk-factors Abca1 and Abca7, could lead to the development of novel therapeutic approaches to prevent neurodegeneration and Alzheimer’s disease.