Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model

Affiliations

¹ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
² Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA.
³ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁴ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁵ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
⁶ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: yadong.huang@gladstone.ucsf.edu.

PMID: 39500314
PMCID: PMC11701721 (available on 2026-01-02)
DOI: 10.1016/j.stem.2024.10.005

Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model

Antara Rao et al. Cell Stem Cell. 2025.

. 2025 Jan 2;32(1):86-104.e7.

doi: 10.1016/j.stem.2024.10.005. Epub 2024 Nov 4.

Authors

Affiliations

¹ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
² Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA.
³ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁴ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁵ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
⁶ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: yadong.huang@gladstone.ucsf.edu.

PMID: 39500314
PMCID: PMC11701721 (available on 2026-01-02)
DOI: 10.1016/j.stem.2024.10.005

Abstract

Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion in a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) iPSC-derived human neurons into the hippocampus of human APOE3 or APOE4 knockin mice and then depleted microglia in half of the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA sequencing analysis identified two pro-inflammatory microglial subtypes with elevated MHC-II gene expression enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.

Keywords: APOE4; Alzheimer’s disease; RNA-seq; amyloid; chimeric disease model; iPSC; microglia; tau; transplantation.

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Conflict of interest statement

Declaration of interests Y. Huang is a cofounder and scientific advisory board member of GABAeron, Inc.

Update of

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model.
Rao A, Chen N, Kim MJ, Blumenfeld J, Yip O, Hao Y, Liang Z, Nelson MR, Koutsodendris N, Grone B, Ding L, Yoon SY, Arriola P, Huang Y. Rao A, et al. bioRxiv [Preprint]. 2023 Nov 14:2023.11.10.566510. doi: 10.1101/2023.11.10.566510. bioRxiv. 2023. Update in: Cell Stem Cell. 2025 Jan 2;32(1):86-104.e7. doi: 10.1016/j.stem.2024.10.005. PMID: 38014339 Free PMC article. Updated. Preprint.

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Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model

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Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model

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