Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist.
1. Neuron. 2024 Feb 7;112(3):384-403.e8. doi: 10.1016/j.neuron.2023.10.023. Epub 2023 Nov 22. Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist. Litvinchuk A(1), Suh JH(2), Guo JL(2), Lin K(2), Davis SS(2), Bien-Ly N(2), Tycksen E(3), Tabor GT(1), Remolina Serrano J(1), Manis M(1), Bao X(1), Lee C(1), Bosch M(1), Perez EJ(1), Yuede CM(1), Cashikar AG(4), Ulrich JD(1), Di Paolo G(5), Holtzman DM(6). Author information: (1)Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA. (2)Denali Therapeutics Inc., South San Francisco, CA 94080, USA. (3)Genome Technology Access Center, McDonnell Genome Institute, St. Louis, MO 63110, USA. (4)Department of Psychiatry, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63108, USA. (5)Denali Therapeutics Inc., South San Francisco, CA 94080, USA. Electronic address: dipaolo@dnli.com. (6)Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA. Electronic address: holtzman@wustl.edu. Erratum in Neuron. 2024 Jun 19;112(12):2079. doi: 10.1016/j.neuron.2024.05.021. Comment in Nat Rev Drug Discov. 2024 Feb;23(2):106. doi: 10.1038/d41573-024-00004-8. Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration. Copyright © 2023 Elsevier Inc. All rights reserved. DOI: 10.1016/j.neuron.2023.10.023 PMCID: PMC10922706 PMID: 37995685 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests D.M.H. is on the scientific advisory board of C2N diagnostics and has equity. D.M.H. is on the scientific advisory board of Denali Therapeutics, Genentech, and Cajal Therapeutics and consults for Asteroid Therapeutics. J.H.S., J.L.G., H.P.B., S.S.D., and G.D.P. are full-time employees and shareholders of Denali Therapeutics Inc. K.L. and N.B.-L. are former employees of Denali Therapeutics Inc.