The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.
Nat Neurosci
; 26(12): 2104-2121, 2023 Dec.
Article
em En
| MEDLINE
| ID: mdl-37957317
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tauopatias
/
Doença de Alzheimer
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article