| First Author | Nelson MR | Year | 2023 |
| Journal | Nat Neurosci | Volume | 26 |
| Issue | 12 | Pages | 2104-2121 |
| PubMed ID | 37957317 | Mgi Jnum | J:343279 |
| Mgi Id | MGI:7564616 | Doi | 10.1038/s41593-023-01480-8 |
| Citation | Nelson MR, et al. (2023) The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci 26(12):2104-2121 |
| abstractText | 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. |
