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Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector
Open accessAbstract
Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-β (Aβ) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD.
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“but late-stage neuropathological features, such as formation of insoluble tau and neurodegeneration have not been reported.”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [17]
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“iPSC-derived neurons from individuals with AD exhibit increased production of Aβ42, active GSK-3β, phosphorylated tau, endosomal abnormalities, and oxidative stress (12–17)”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [17]
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In the citing paper
“It exacerbates AD-related pathologies, including amyloid-beta (Aβ) plaques, Tau tangles, neurodegeneration and neuroinflammation4–16.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Research in animal models (Bien-Ly et al., 2012) and hiPSC-based models (Wang et al., 2018) has indicated that the APOE3 genotype leads to higher total APOE levels compared to the APOE4 genotype.”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Wang et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Previous studies with mouse (Andrews-Zwilling et al., 2010) and hiPSC-based (Wang et al., 2018) systems have shown that APOE genotypes might influence GABAergic interneuron generation and survival.”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Wang et al., 2018
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“Likewise, APOE3ch did not affect APOE secretion, consistent with prior work demonstrating that APOE stability and secretion are primarily isoform-dependent (E4 < E3 < E2) (Bien-Ly et al., 2012; Wang et al., 2018) and that the Christchurch R136S substitution likely influences receptor-binding and HSPG interactions rather than secretion pathways.”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Wang et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Multiple small molecules have been designed to ‘correct’ the conformation of APOE4 so that it resembles that of APOE3 or APOE2 (refs. 213–217)”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [217]
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“Some of these molecules have been shown to be effective in cell models, whereas others are in even earlier stages of development216,217.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [217]
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In the citing paper
“Studies with human iPSC-derived neurons and organoids confirm that apoE4 increases Aβ production and aggregation as well as decreases Aβ clearance”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Wang et al 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Studies with human iPSC-derived neurons and cerebral organoids demonstrate that apoE4 enhances tau phosphorylation and exacerbates synapse loss and neurodegeneration”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Wang et al 2018
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“Isogenic APOE4/4 and APOE3/3 iPS cells were generated as previously described16.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [16]
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“As reported previously6, the E4 neuron culture had a lower fraction of GABA+ inhibitory neurons than the E3 neuron culture (Supplementary Fig. 2c,d).”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [6]
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“Western blotting analysis of cell lysates with PHF1 and AT8 antibodies revealed that the E3 neurons had a significant reduction in p-Tau levels compared to E4 neurons (Fig. 2a,c,d and Supplementary Fig. 3b,c), confirming our previous report6.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“Immunocytochemistry analysis confirmed that MAP2+ neurons expressed APOE (Supplementary Fig. 2a), as reported previously6.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“hiPSC lines were then differentiated into neurons expressing mature neuronal marker MAP2 (Extended Data Fig. 3c) via an optimized method using dual-SMAD inhibition6,56.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [6]
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“Such correctors have already been shown to restore ApoE3-like behavior in iPSC-derived neurons (37,48)”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [48]
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In the citing paper
“We also observe apoptotic pathways, including activation of BH3-only proteins (Reactome:R-HSA-114452) and apoptosis (Reactome:R-HSA-109581, Supp. Table S36), suggesting a potential role of APOE40–42 in cell death.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [41]
The cited source says what the claim attributes to it.
In the citing paper
“Additionally, treating ApoE4-expressing iPSC-derived neurons with PH002, another structure corrector, was able to ameliorate the toxic effects induced by this isoform of ApoE, by reducing ApoE4 detrimental effect on neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons [85], increasing the number of GABAergic neurons and reducing P-tau, Aβ40 and Aβ42 levels [86].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“Additionally, treating ApoE4-expressing iPSC-derived neurons with PH002, another structure corrector, was able to ameliorate the toxic effects induced by this isoform of ApoE, by reducing ApoE4 detrimental effect on neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons [85], increasing the number of GABAergic neurons and reducing P-tau, Aβ40 and Aβ42 levels [86].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“Similar co-regulation of Aβ and Tau through independent pathways have recently been shown for ApoE (Wang et al., 2018) and the retromer complex (Young et al., 2018).”
From Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons (2019) · cites this paper as Wang et al., 2018
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“suggesting that the R136S mutation results in less APOE4 fragmentation6.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [6]
Experimental — accuracy not yet measuredIn the citing paper
“For example, apoE4/4 neurons produced significantly more Aβ and phosphorylated tau than apoE3/3 neurons.”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [128]
In the citing paper
“Strikingly, much of AD pathology seen in vivo was successfully recapitulated in this hiPSC-derived neuronal model in vitro.”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [128]
In the citing paper
“the use of a structure corrector has been shown in vitro to ameliorate apoE4-mediated AD pathologies in hiPSC-derived neurons, including GABAergic neuron deficits [128].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [128]
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Metadata
- Authors
- Wang, C., Najm, R., Xu, Q., Jeong, D.-E., Walker, D., Balestra, M. E., Yoon, S. Y., Yuan, H., Li, G., Miller, Z. A., Miller, B. L., Malloy, M. J., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- University of California, San Francisco (US)
- Corresponding author
- Huang, Yadong
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-04-09
- Volume
- 24
- Issue
- 5
- Pages
- 647-657
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5948154
- OpenAlex
- W2798230823
- Cited by
- 428
- References
- 62
- Citations by year
- 2026: 36 · 2025: 45 · 2024: 69 · 2023: 57 · 2022: 54 · 2021: 48 · 2020: 58 · 2019: 42 · 2018: 18
- FWCI
- 28.54
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- California Institute for Regenerative Medicine (TRAN1-09394, RN2-00952)
- Roddenberry Foundation
- National Institutes of Health (AG023501)
- National Institute on Aging (RF1AG048030, R01AG056305, K23AG048291, R01AG048017, P50AG023501)
- National Institute of Allergy and Infectious Diseases (P30AI027763)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, Alzheimer's disease, gain-of-function, iPSC-derived neurons, tau phosphorylation, amyloid-beta production, genome editing, APOE3, human disease models, therapeutic target
- MeSH terms
- Gene Editing, Alzheimer Disease, Cell Line, Cells, Cultured, Homozygote, Humans, Nerve Degeneration, Neurons, Phosphorylation, Amyloid beta-Peptides, tau Proteins, Protein Isoforms, Apolipoprotein E3, Apolipoprotein E4, Small Molecule Libraries, Induced Pluripotent Stem Cells, GABAergic Neurons
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