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Cited by 142Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease

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Wadhwani, Anil R., Affaneh, Amira, Van Gulden, Stephanie, Kessler, John A.·2019·Annals of Neurology
DOI 10.1002/ana.25455PMC PMC8123085
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Abstract

Objective: The apolipoprotein E ( APOE ) E4 isoform is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Although APOE is predominantly expressed by astrocytes in the central nervous system, neuronal expression of APOE is of increasing interest in age‐related cognitive impairment, neurological injury, and neurodegeneration. Here, we show that endogenous expression of E4 in stem‐cell–derived neurons predisposes them to injury and promotes the release of phosphorylated tau. Methods: Induced pluripotent stem cells from 2 unrelated AD patients carrying the E4 allele were corrected to the E3/E3 genotype with the CRISPR/Cas9 system and differentiated into pure cultures of forebrain excitatory neurons without contamination from other cells types. Results: Compared to unedited E4 neurons, E3 neurons were less susceptible to ionomycin‐induced cytotoxicity. Biochemically, E4 cells exhibited increased tau phosphorylation and ERK1/2 phosphoactivation. Moreover, E4 neurons released increased amounts of phosphorylated tau extracellularly in an isoform‐dependent manner by a heparin sulfate proteoglycan–dependent mechanism. Interpretation: Our results demonstrate that endogenous expression of E4 by stem‐cell–derived forebrain excitatory neurons predisposes neurons to calcium dysregulation and ultimately cell death. This change is associated with increased cellular tau phosphorylation and markedly enhanced release of phosphorylated tau. Importantly, these effects are independent of glial APOE. These findings suggest that E4 accelerates spreading of tau pathology and neuron death in part by neuron‐specific, glia‐independent mechanisms. Ann Neurol 2019;85:726–739

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  • ApoE4 accelerates tau pathology spreading particularly when secreted by neurons.

    “or accelerate tau pathology spreading particularly when secreted by neurons [50]”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [50]

    The Abstract’s Interpretation and Discussion suggest that neuronal E4 increases phosphorylated-tau release and may accelerate the spread of tau pathology. But the Discussion says further experiments are needed to determine whether APOE secretion is involved; the paper does not establish that the effect occurs particularly when E4 itself is secreted by neurons. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • These alterations were accompanied by increased P-tau neuronal release and accelerated tau spreading.

    “These alterations were accompanied by increased P-tau neuronal release and accelerated tau spreading”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [50]

    The Results report increased neuronal release of phosphorylated tau from E4 neurons. The Discussion describes faster spread of tau pathology in patients with the E4 allele, but proposes—rather than demonstrates—that enhanced neuronal p-tau release contributes to that spread. The paper does not show that the measured alterations were accompanied by accelerated spreading in its neuronal cultures. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Association between ApoE4 expression and mitochondrial Ca2+ overload was observed in in vitro models, such as Neuro-2 A cells, stem-cell-derived forebrain excitatory neurons and rat hippocampal neurons.

    “an association between ApoE4 expression and mitochondrial Ca2+ overload was observed in in vitro models, such as Neuro-2 A cells [28,73], stem-cell-derived forebrain excitatory neurons [50] and rat hippocampal neurons [30].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [50]

    The Results (page unavailable) show that ApoE4-expressing stem-cell-derived forebrain excitatory neurons were more susceptible than isogenic E3 neurons to ionomycin-induced calcium dysregulation and cell death. The paper does not report mitochondrial Ca2+ overload in those neurons, so the mitochondrial-specific part attributed to this source is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Neuronal ApoE4 is associated with increased neuronal vulnerability to cytotoxicity, Ca2+ dysregulation and cell death in iPSCs derived from AD patients carrying the APOE ε4 allele.

    “neuronal ApoE4 was proven to be associated to increased neuronal vulnerability to cytotoxicity, Ca2+ dysregulation and cell death, in iPSCs derived from AD patients carrying the APOE ε4 allele.”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [50]

  • ApoE4 accelerates tau pathology propagation through a trans-synaptic prion-like mechanism.

    “which supports the hypothesis that ApoE4 accelerates tau pathology propagation, through a trans-synaptic prion-like mechanisms [50].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [50]

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Cited by

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Authors
Wadhwani, A. R., Affaneh, A., Van Gulden, S., & Kessler, J. A.
Affiliations
  • Northwestern University (US)
  • Department of Neurology Northwestern University Chicago IL
Corresponding author
Wadhwani, Anil R.
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2019-03-27
Volume
85
Issue
5
Pages
726-739
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.25455
PMC
PMC8123085
OpenAlex
W2921297416
Cited by
142
References
22
Citations by year
2026: 7 · 2025: 29 · 2024: 21 · 2023: 11 · 2022: 21 · 2021: 25 · 2020: 23 · 2019: 5
FWCI
12.56
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (R01AG054429, F30AG051327, T32AG20506, T32GM008152)
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, tau phosphorylation, excitatory neurons, calcium dysregulation, ERK1/2 activation, heparan sulfate proteoglycans, CRISPR/Cas9 genome editing, induced pluripotent stem cells, neuronal cell death
MeSH terms
Alzheimer Disease, Female, Humans, Male, Neurons, Phosphorylation, tau Proteins, Cell Death, Apolipoprotein E4, Induced Pluripotent Stem Cells

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