ArticleMolecular neurodegeneration2025
APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology.
Article in Molecular neurodegeneration, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Therapeutic potential and underlying mechanisms of engineered young plasma-derived exosomes in Alzheimer's disease.Bioactive materials · 2027Article
- CXCL10 contributes to female-specific pathological progression in tauopathy model mice.Journal of neuroinflammation · 2026Article
- Protective mutations associated with APOE in Alzheimer's disease.Molecular psychiatry · 2026Review
- Acute viral encephalitis impacts dense-core amyloid plaque pathology and dysregulates myeloid responses to amyloid plaques.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Integrated imaging and molecular profiling reveals APOE4-associated neurovascular and glial disruptions in young adult mice.Journal of neuroinflammation · 2026Article
- Abi3Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Advances in hiPSC-Derived Brain Organoids as a Model to Study Neuroinflammation in Alzheimer's Disease.Journal of neurochemistry · 2026Review
- A critical appraisal of the link between apolipoprotein E and Tau.Current opinion in neurology · 2026Review
- Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice.Translational psychiatry · 2026Article
- A strategy of microglia replacement alleviates microgliopathy in a CSF1R I794T hotspot mutation mouse model of CSF1R-related disorder.Cell reports. Medicine · 2026Article
- Characterization of effects of a neurotropic murine coronavirus infection on Alzheimer's disease neuropathology of 5xFAD mice.bioRxiv : the preprint server for biology · 2026Article
- APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.Frontiers in molecular biosciences · 2026Article
- The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies.bioRxiv : the preprint server for biology · 2025Article
- APOE4 promotes nigral tau hyperphosphorylation through cholesterol in atherosclerosis.Cell death discovery · 2025Article
- Trends and challenges of AAV-delivered gene editing therapeutics for CNS disorders: Implications for neurodegenerative disease.Molecular therapy. Nucleic acids · 2025Review
- Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health.Nature communications · 2025Article
- Identification of the velum interpositum as a meningeal-CNS route for myeloid cell trafficking into the brain.Neuron · 2025Article
- Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease.bioRxiv : the preprint server for biology · 2024Article
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Abstract
backgroundApolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.
methodsWe introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain's response to plaques and tau.
resultsIn 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice.
conclusionsThese findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.
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