The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.

Autor: Nelson MR; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA., Liu P; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA., Agrawal A; Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA., Yip O; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA., Blumenfeld J; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA., Traglia M; Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA., Kim MJ; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA., Koutsodendris N; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA., Rao A; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA., Grone B; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA., Hao Y; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA., Yoon SY; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA., Xu Q; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA., De Leon S; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA., Choenyi T; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA., Thomas R; Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA., Lopera F; Grupo de Neurociencias de Antioquia de la Universidad de Antioquia, Medellin, Colombia., Quiroz YT; Grupo de Neurociencias de Antioquia de la Universidad de Antioquia, Medellin, Colombia.; Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Arboleda-Velasquez JF; Schepens Eye Research Institute of Mass Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Reiman EM; Banner Alzheimer's Institute, Phoenix, AZ, USA.; University of Arizona, Tucson, AZ, USA., Mahley RW; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Huang Y; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA. yadong.huang@gladstone.ucsf.edu.; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA. yadong.huang@gladstone.ucsf.edu.; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA. yadong.huang@gladstone.ucsf.edu.; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA. yadong.huang@gladstone.ucsf.edu.; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA. yadong.huang@gladstone.ucsf.edu.; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. yadong.huang@gladstone.ucsf.edu.; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. yadong.huang@gladstone.ucsf.edu.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2023 Dec; Vol. 26 (12), pp. 2104-2121. Date of Electronic Publication: 2023 Nov 13.
DOI: 10.1038/s41593-023-01480-8
Abstrakt: Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.
(© 2023. The Author(s).)
Databáze: MEDLINE
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