Cited by 9Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Inhibitory Roles of Apolipoprotein E Christchurch Astrocytes in Curbing Tau Propagation Using Human Pluripotent Stem Cell-Derived Models

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Murakami, Rei, Watanabe, Hirotaka, Hashimoto, Hideko, Kashiwagi-Hakozaki, Mayu, Hashimoto, Tadafumi, Karch, Celeste M., the Dominantly Inherited Alzheimer Network (DIAN),, Iwatsubo, Takeshi +1 more·2024·The Journal of Neuroscience

Abstract

Genetic variants in the apolipoprotein E ( APOE ) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch ( APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3 Ch/ 3 Ch human-induced pluripotent stem cells (iPSCs) from APOE3 / 3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3 Ch/ 3 Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3 / 3 astrocytes, but not in APOE3 Ch/ 3 Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3 Ch/ 3 Ch astrocytes reduced complexity compared with APOE3 / 3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3 Ch/ 3 Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research.

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Registry

Crossref · 10.1523/jneurosci.1709-23.2024

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  • Murakami et al. reported no genotype-dependent differences in lipid droplet accumulation or apoE secretion in similarly differentiated iPSC-derived APOE3-Ch astrocytes.

    “Our results differ from those of Murakami et al., 37 who used similarly differentiated iPSC‐derived APOE3‐Ch astrocytes but reported no genotype‐dependent differences in lipid droplet accumulation or apoE secretion.”

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Authors
Murakami, R., Watanabe, H., Hashimoto, H., Kashiwagi-Hakozaki, M., Hashimoto, T., Karch, C. M., the Dominantly Inherited Alzheimer Network (DIAN), Iwatsubo, T., & Okano, H.
Affiliations
  • Keio University (JP)
  • National Center of Neurology and Psychiatry (JP)
  • Washington University in St. Louis (US)
Venue
The Journal of Neuroscience
Published
2024-04-22
Volume
44
Issue
24
Pages
e1709232024
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W4394994802
Cited by
9
References
49
Citations by year
2026: 3 · 2025: 6
FWCI
2.56
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders
  • Japan Agency for Medical Research and Development (JP17pc0101006)
  • MEXT | Japan Society for the Promotion of Science (JP21H05633, 22J11065)
  • HHS | NIH | National Institute on Aging (U19AG032438)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
apolipoprotein E, APOE3, astrocytes, tau propagation, Alzheimer's disease, human induced pluripotent stem cells, iPSC-derived neurons, astrocyte-neuron co-culture, astrocyte activation, inflammatory cytokines, astrocyte morphology, sex differences
MeSH terms
Alzheimer Disease, Apolipoproteins E, Astrocytes, Cells, Cultured, Female, Humans, Neurons, tau Proteins, Coculture Techniques, Apolipoprotein E3, Induced Pluripotent Stem Cells

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