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Cited by 52Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsPluripotent Stem Cells Research

In Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons

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Najm, Ramsey, Zalocusky, Kelly A., Zilberter, Misha, Yoon, Seo Yeon, Hao, Yanxia, Koutsodendris, Nicole, Nelson, Maxine, Rao, Antara +3 more·2020·Cell Reports
DOI 10.1016/j.celrep.2020.107962PMC PMC7430173
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Abstract

Despite its clear impact on Alzheimer's disease (AD) risk, apolipoprotein (apo) E4's contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplant human induced pluripotent stem cell (hiPSC)-derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knockin mouse hippocampi, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single-nucleus RNA sequencing (snRNA-seq), we identify key transcriptional changes specific to human neuron subtypes in response to endogenous or exogenous apoE4. We also find that Aβ from transplanted human neurons forms plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype. These findings highlight the power of in vivo chimeric disease modeling for studying AD.

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Authors
Najm, R., Zalocusky, K. A., Zilberter, M., Yoon, S. Y., Hao, Y., Koutsodendris, N., Nelson, M., Rao, A., Taubes, A., Jones, E. A., & Huang, Y.
Affiliations
Gladstone Institutes (US)
Corresponding author
Huang, Yadong
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2020-07
Volume
32
Issue
4
Pages
107962
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2020.107962
PMC
PMC7430173
OpenAlex
W3045806571
Cited by
52
References
119
Citations by year
2026: 8 · 2025: 11 · 2024: 4 · 2023: 14 · 2022: 10 · 2021: 4 · 2020: 1
FWCI
4.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
  • James B. Pendleton Charitable Trust
  • National Institutes of Health (S10 RR028962)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
Alzheimer's disease, APOE ε4, human induced pluripotent stem cell-derived neurons, single-nucleus RNA sequencing, amyloid plaques, microglia, in vivo transplantation
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Chimera, Hippocampus, Humans, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Neurons, Amyloid beta-Peptides, tau Proteins, Microglia, Mice, Apolipoprotein E3, Apolipoprotein E4, Gene Knock-In Techniques, Induced Pluripotent Stem Cells

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