ArticleNature aging2026
Neuronal APOE4-induced early hippocampal network hyperexcitability in Alzheimer's disease pathogenesis.
Article in Nature aging, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Input-output curves demonstrate motor cortex hyperexcitability associated with cognitive impairment in Alzheimer's disease.Neurobiology of aging · 2026Article
- ApoE4 as a Therapeutic Target in Epilepsy: From Pathogenic Mechanisms to Precision Medicine.CNS neuroscience & therapeutics · 2026Review
- Review
- Ontological Analysis of Brain Proteostasis Highlights the Sex-Dependent Trajectory of ApoE Isoform-Specific Regulation.bioRxiv : the preprint server for biology · 2026Article
- Deciphering the functions of NELL2 in tumorigenesis and beyond.Frontiers in immunology · 2026Review
- Microglia-to-neuron signaling linksProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Microglia-to-neuron signaling increases lipid droplet metabolism, enhancing neuronal network activity.bioRxiv : the preprint server for biology · 2025Article
- Article
- CRISPRi-based screens in iAssembloids to elucidate neuron-glia interactions.bioRxiv : the preprint server for biology · 2024Article
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20 authors.
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Abstract
The full impact of APOE4 (apolipoprotein E4), the strongest genetic risk factor for Alzheimer's disease (AD), on neuronal and network function remains unclear, particularly during early preclinical stages of disease. Here we show that young APOE4 knockin (E4-KI) mice exhibit hippocampal region-specific network hyperexcitability that predicts later cognitive deficits. This early phenotype arises from cell-type-specific subpopulations of smaller, hyperexcitable neurons and is eliminated by selective removal of neuronal APOE4. With aging, E4-KI mice develop granule cell hyperexcitability, progressive inhibitory dysfunction and excitation-inhibition imbalance in the dentate gyrus. Single-nucleus RNA sequencing with multilevel gene filtering reveals age-dependent and cell-type-specific transcriptional changes and identifies candidate mediators of early neuronal hyperexcitability, including Nell2. Targeted CRISPR interference knockdown of Nell2 rescues abnormal excitability, implicating Nell2 as a contributor to APOE4-driven dysfunction. Together, these findings define molecular and circuit mechanisms linking neuronal APOE4-induced early network impairment to AD pathogenesis with aging.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.