ArticleCNS neuroscience & therapeutics2025
Sequential Proteomic Analysis Reveals the Key APOE4-Induced Pathological and Molecular Features at the Presymptomatic Stage in Alzheimer's Disease Mice.
Article in CNS neuroscience & therapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Ontological Analysis of Brain Proteostasis Highlights the Sex-Dependent Trajectory of ApoE Isoform-Specific Regulation.bioRxiv : the preprint server for biology · 2026Article
- The impact of APOE genotype, age, and sex on gut microbiota in a mouse model of Alzheimer's Disease: an exploration of their interactions.Biology of sex differences · 2026Article
- Apolipoprotein E4 in Alzheimer's Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment.International journal of molecular sciences · 2026Review
- Toward a Unified Framework in Molecular Neurobiology of Alzheimer's Disease: Revisiting the Pathophysiological Hypotheses.Molecular neurobiology · 2025Review
- Potentiating Cerebral Perfusion Normalizes Glymphatic Dynamics in Systemic Inflammation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions.Acta pharmaceutica Sinica. B · 2025Review
- The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.Cell death discovery · 2025Review
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Authors and funding
7 authors.
Funding
Abstract
aimsAlzheimer's disease (AD) involves a prolonged presymptomatic or preclinical stage with subtle pathological changes. Apolipoprotein E4 (APOE4) is a significant genetic risk factor for AD, yet its specific role at the presymptomatic stage is not fully understood. This study aimed to elucidate the cellular and molecular effects of APOE4 compared to APOE3 on AD progression during the presymptomatic stage.
methodsWe generated 5xFAD AD mice carrying human APOE3 or APOE4 and their non-AD controls. Behavioral tests, immunostaining, quantitative proteomics and phosphoproteomics, Golgi staining, and Western blotting were conducted at 3 or 10 months of age, respectively. Cell culture experiments were performed to assess APOE4's direct impact on neuronal mitochondrial function.
resultsAPOE4 significantly increased β-amyloid (Aβ) deposition and microglial activation compared to APOE3 in 5xFAD mice at the presymptomatic stage, without aggravating the blood-brain barrier disruption. Proteomic and biochemical analysis revealed strong molecular features of synaptic degeneration and mitochondrial dysfunction associated with APOE4. Notably, APOE4 promoted mitochondrial fusion and mitophagy while inhibiting fission, leading to impaired neuronal energy supply and increased reactive oxygen species.
conclusionOur findings indicate that APOE4 accelerates AD pathologies at the presymptomatic stage by exacerbating Aβ deposition, neuroinflammation, and synaptic degeneration. The study highlights mitochondrial dysfunction as a critical mediator of APOE4-induced AD progression, providing potential targets for early intervention.
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