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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Late-stage neuropathological features, such as formation of insoluble tau and neurodegeneration, have not been reported in iPSC-derived neurons from individuals with AD.
“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]
The Results section, “ApoE4 causes GABAergic neuron degeneration/loss in hiPSC-derived neuronal culture” (page unavailable), reports degeneration and apoptotic death in human iPSC-derived GABAergic neurons—contrary to the claim that neurodegeneration has not been reported. The passages report phosphorylated tau, but do not establish formation of insoluble tau. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measurediPSC-derived neurons from individuals with AD exhibit increased production of Aβ42, active GSK-3β, phosphorylated tau, endosomal abnormalities, and oxidative stress.
“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]
The Results report increased Aβ42 secretion and phosphorylated tau in human iPSC-derived apoE4/4 neurons compared with apoE3/3 neurons. The paper does not report increased active GSK-3β, endosomal abnormalities, or oxidative stress in those neurons; its comparison is by apoE genotype, not broadly between individuals with and without AD. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE4 exacerbates AD-related pathologies, including amyloid-beta plaques, Tau tangles, neurodegeneration and neuroinflammation.
“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]
The Introduction associates apoE4 with increased amyloid plaques and tau tangles. The Discussion reports increased Aβ production, tau phosphorylation, and GABAergic neuron degeneration in apoE4 cultures. The passages do not address neuroinflammation, so that part of the claim is unsupported by this source. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAPOE3 genotype leads to higher total APOE levels compared to APOE4 genotype.
“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
The Results section on apoE production (page unavailable) reports that apoE4/4 hiPSC-derived neurons had less full-length intracellular and secreted apoE than apoE3/3 neurons. It also reports more apoE fragments in apoE4/4 neurons, so the comparison supports higher full-length apoE with APOE3 but does not establish higher total apoE across full-length protein and fragments. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPOE genotypes might influence GABAergic interneuron generation and survival.
“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
The Results section reports greater degeneration and apoptotic death of APOE4/4-derived GABAergic neurons than APOE3/3-derived neurons, supporting an effect on survival. It also reports no early difference in GABA-positive neuron numbers and says the effect is not developmental, so this study does not support an effect on interneuron generation. (LLM, conf=0.88)
Experimental — accuracy not yet measured
APOE3ch did not affect APOE secretion.
“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
The Results section on full-length apoE (page unavailable) reports that human apoE4/4 neurons secrete about 60% less full-length apoE than apoE3/3 neurons, supporting the E4 < E3 portion of the cited background statement. It does not establish the comparison with E2 or directly measure apoE stability. The paper does not study APOE3ch, but the citation is attached to the background statement rather than the citing authors’ APOE3ch finding. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMultiple small molecules have been designed to correct the conformation of APOE4 so that it resembles that of APOE3 or APOE2.
“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]
The Results section says the authors identified multiple small-molecule structure correctors that make APOE4 structurally and functionally APOE3-like, and tested one of them, PH002. It does not say that the correctors make APOE4 resemble APOE2. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSome of these molecules have been shown to be effective in cell models, whereas others are in even earlier stages of development.
“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]
The Results section (page unavailable) reports that the small-molecule structure corrector PH002 ameliorated several pathological effects in human iPSC-derived neurons, supporting effectiveness in a cell model. The paper does not establish that other molecules are at earlier stages of development. (LLM, conf=0.85)
Experimental — accuracy not yet measuredHuman iPSC-derived neurons and organoids confirm that apoE4 increases Aβ production and aggregation and decreases Aβ clearance.
“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
The Results section, “Human apoE4/4 neurons produce more Aβ than human apoE3/3 neurons” (page unavailable), reports that human iPSC-derived apoE4/4 neurons secreted more than twice as much Aβ40 and Aβ42 as apoE3/3 neurons. It does not report organoid experiments or show increased Aβ aggregation or decreased clearance in those neurons. The reduced-clearance finding is described there and in the Discussion as a finding from mouse studies, not this paper’s human-neuron experiments. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHuman iPSC-derived neurons and cerebral organoids demonstrate that apoE4 enhances tau phosphorylation and exacerbates synapse loss and neurodegeneration.
“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
The Results sections on phosphorylated tau and GABAergic neuron loss report higher p-tau levels and degeneration in human iPSC-derived apoE4 neurons. The passages do not establish synapse loss or findings from cerebral organoids; the reported experiments used neuronal cultures. Page numbers were not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIsogenic APOE4/4 and APOE3/3 iPS cells were used.
“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]
The E4 neuron culture had a lower fraction of GABA+ inhibitory neurons than the E3 neuron culture.
“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]
E3 neurons had a significant reduction in p-Tau levels compared to E4 neurons.
“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]
MAP2+ neurons expressed APOE.
“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]
hiPSC lines were differentiated into neurons expressing mature neuronal marker MAP2 via dual-SMAD inhibition.
“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]
Small-molecule structure correctors have been shown to restore ApoE3-like behavior in iPSC-derived neurons.
“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]
The study also observed apoptotic pathways, including activation of BH3-only proteins and apoptosis, suggesting a potential role of APOE in cell death.
“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]
Treating ApoE4-expressing iPSC-derived neurons with PH002 ameliorated the toxic effects induced by ApoE4.
“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]
PH002 treatment increased the number of GABAergic neurons and reduced P-tau, Aβ40 and Aβ42 levels.
“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 R136S mutation results in less APOE4 fragmentation.
“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]
The Results report less apoE fragmentation after gene editing converted apoE4 to apoE3, but do not identify that change as R136S. Searches for R136S and Arg136Ser found no passage testing or discussing that mutation’s effect on fragmentation. The cited paper therefore does not establish the specific claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredApoE4/4 neurons produced significantly more amyloid-β and phosphorylated tau than apoE3/3 neurons.
“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]
Much of the Alzheimer's disease pathology seen in vivo was successfully recapitulated in a human induced pluripotent stem cell-derived neuronal model in vitro.
“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]
Use of a structure corrector ameliorates apoE4-mediated AD pathologies in hiPSC-derived neurons, including GABAergic neuron deficits.
“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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- 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
- Health Sciences › Medicine › Physiology › 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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