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APOE4 Increases Systemic Inflammation and Alters Metabolic and Neuroprotective Pathways following Multiagent Chemotherapy in Older Human APOE Knock-In Mice

ABSTRACT: Spatial transcriptomic profiling of APOE4 mice post-chemotherapy compared with APOE3 knock-in mice to assess genotype-specific regional gene expression changes.

ORGANISM(S): Mus musculus

PROVIDER: GSE328853 | GEO | 2026/04/27

REPOSITORIES: GEO

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Project description: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. 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.

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APOE4 Increases Systemic Inflammation and Alters Metabolic and Neuroprotective Pathways following Multiagent Chemotherapy in Older Human APOE Knock-In Mice

Project description:APOE4 Increases Systemic Inflammation and Alters Metabolic and Neuroprotective Pathways following Multiagent Chemotherapy in Older Human APOE Knock-In Mice

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