151. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.
- Author
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Nelson, Maxine, Liu, Peng, Agrawal, Ayushi, Yip, Oscar, Blumenfeld, Jessica, Traglia, Michela, Kim, Min, Koutsodendris, Nicole, Rao, Antara, Grone, Brian, Hao, Yanxia, Yoon, Seo, Xu, Qin, De Leon, Samuel, Choenyi, Tenzing, Thomas, Reuben, Lopera, Francisco, Quiroz, Yakeel, Arboleda-Velasquez, Joseph, Reiman, Eric, Mahley, Robert, and Huang, Yadong
- Subjects
Animals ,Humans ,Mice ,Alzheimer Disease ,Apolipoprotein E3 ,Apolipoprotein E4 ,Mutation ,Neuroinflammatory Diseases ,Tauopathies - Abstract
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimers 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.
- Published
- 2023