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Gladstone Institutes, 현 Stanford University

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Nature Aging, 03 April 2026 | https://doi.org/10.1038/s43587-026-01096-0 Neuronal APOE4-induced early hippocampal network hyperexcitability in Alzheimer’s disease pathogenesis

Dennis R. Tabuena^1,8, Sung-Soo Jang^1,8, Brian Grone^1,2,8, Oscar Yip^1,3, Emily A. Aery Jones ¹, Jessica Blumenfeld^1,4, Zherui Liang^1,4, Rajkamalpreet S. Mann¹, Yaqiao Li ^1,2, Deanna Necula^1,4, Nicole Koutsodendris^1,5, Antara Rao ^1,5, Leonardo Ding ¹, Alex R. Zhang¹, Yanxia Hao^1,2, Qin Xu^1,2, Seo Yeon Yoon¹, Samuel De Leon¹, Yadong Huang^{1,2,3,4,5,6,7} & Misha Zilberter¹

¹Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
²Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA.
³Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA, USA.
⁴Neuroscience Program, University of California, San Francisco, San Francisco, CA, USA.
⁵Developmental and Stem Cell Biology Program, University of California, San Francisco, San Francisco, CA, USA.
⁶Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁷Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
⁸These authors contributed equally: Dennis R. Tabuena, Sung-Soo Jang, Brian Grone.

Corresponding authors
Correspondence to Yadong Huang or Misha Zilberter.

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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