Neuronal APOE4-induced early hippocampal network hyperexcitability in Alzheimer's disease pathogenesis - PubMed
7 hours ago
- #APOE4
- #Alzheimer's Disease
- #Hippocampal Hyperexcitability
- APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), but its early impact on neuronal and network function is unclear.
- Young APOE4 knockin mice show hippocampal network hyperexcitability, which predicts later cognitive deficits and originates from specific subpopulations of smaller, hyperexcitable neurons.
- Removing neuronal APOE4 eliminates this early hyperexcitability, indicating a direct role of APOE4 in neuronal dysfunction.
- Aged APOE4 knockin mice develop further excitability issues, including granule cell hyperexcitability and progressive inhibitory dysfunction in the dentate gyrus.
- Single-nucleus RNA sequencing identifies age-dependent transcriptional changes and Nell2 as a candidate mediator of early hyperexcitability.
- CRISPR interference knockdown of Nell2 rescues abnormal excitability, confirming its role in APOE4-driven dysfunction.
- The study links neuronal APOE4-induced early network impairment to AD pathogenesis through molecular and circuit mechanisms.