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[Preprint]. 2024 Jul 3:2023.08.28.555153. Originally published 2023 Aug 29. [Version 3] doi: 10.1101/2023.08.28.555153

Neuronal APOE4-induced Early Hippocampal Network Hyperexcitability in Alzheimer’s Disease Pathogenesis

Dennis R Tabuena, Sung-Soo Jang, Brian Grone, Oscar Yip, Emily A Aery Jones, Jessica Blumenfeld, Zherui Liang, Nicole Koutsodendris, Antara Rao, Leonardo Ding, Alex R Zhang, Yanxia Hao, Qin Xu, Seo Yeon Yoon, Samuel De Leon, Yadong Huang, Misha Zilberter
PMCID: PMC10491126  PMID: 37693533

ABSTRACT

The full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific network hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network hyperexcitability in young E4-KI mice was mediated by hippocampal region-specific subpopulations of smaller and hyperexcitable neurons that were eliminated by selective removal of neuronal APOE4. Aged E4-KI mice exhibited hyperexcitable granule cells, a progressive inhibitory deficit, and E/I imbalance in the dentate gyrus, exacerbating hippocampal hyperexcitability. Single-nucleus RNA-sequencing revealed neuronal cell type-specific and age-dependent transcriptomic changes, including Nell2 overexpression in E4-KI mice. Reducing Nell2 expression in specific neuronal types of E4-KI mice with CRISPRi rescued their abnormal excitability phenotypes, implicating Nell2 overexpression as a cause of APOE4-induced hyperexcitability. These findings highlight the early transcriptomic and electrophysiological alterations underlying APOE4-induced hippocampal network dysfunction and its contribution to AD pathogenesis with aging.

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