Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits
Open accessAbstract
Apolipoprotein E4 ( APOE4 ) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.
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PS19-E4 mice displayed roughly two-fold higher AT8+ p-Tau coverage area in the hippocampus than PS19-E3 mice.
“PS19-E4 mice displayed roughly two-fold higher AT8+ p-Tau coverage area than PS19-E3 mice (Fig. 1b,c), as reported previously7,55.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [55]
The Results section ('Removal of APOE4 from neurons drastically reduces tau pathology'; page unavailable) reports that AT8 staining showed significantly more tau pathology throughout the hippocampus in PS19-fE4 mice than in PS19-fE3 mice. Our copy does not state that AT8-positive coverage area was roughly two-fold higher, so the magnitude is not verified. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPS19-E4 mice exhibited significantly reduced hippocampal volume compared to WT and PS19-E3 mice.
“PS19-E4 mice exhibited significantly reduced hippocampal volume compared to WT and PS19-E3 mice (Fig. 4a,b and Extended Data Fig. 2a), as reported previously7,55.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [55]
The Results section, “Neurodegeneration is reduced after removal of neuronal APOE4” (page unavailable), reports greater neurodegeneration in PS19-fE4 than PS19-fE3 mice based on hippocampal and ventricular volumes. It does not report the claimed hippocampal-volume comparison with WT mice, so that part is unsupported by this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn 10-month-old PS19-E4 mice, AT8 percent coverage area was negatively correlated with hippocampal volume.
“In 10-month-old PS19-E4 mice, the AT8 (p-Tau) percent coverage area was negatively correlated with hippocampal volume (Fig. 4f), as shown previously7,55, indicating a deleterious role of p-Tau in hippocampal degeneration.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [55]
Microgliosis contributes to hippocampal degeneration.
“suggesting the contribution of microgliosis to hippocampal degeneration, as reported in previous studies7,55”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [55]
Some neurons and oligodendrocytes also express APOE.
“Some neurons and oligodendrocytes also express APOE”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [55]
APOE4 exacerbates these phenotypes in a PS19 tauopathy model.
“APOE4 exacerbates these phenotypes in a PS19 tauopathy model7,11,55.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [55]
Sample sizes for mouse snRNA-seq studies were determined by a power analysis based on effect sizes from previous studies and literature.
“Sample sizes for mouse snRNA-seq studies were determined by a power analysis based on effect sizes from our previous studies22,55 and literature.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [55]
Removing APOE4 from neurons in a tauopathy mouse model leads to a significant reduction in tau neurofibrillary tangle pathology and tau-induced neurodegeneration.
“removing APOE4 from neurons in a tauopathy mouse model leads to a significant reduction in tau neurofibrillary tangle pathology and tau-induced neurodegeneration161.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [161]
APOE4 drives Aβ- and tau-mediated neurodegeneration by inducing microglial and astrocytic activation.
“Studies have demonstrated that APOE4 drives Aβ- and tau-mediated neurodegeneration by inducing microglial and astrocytic activation.174–179”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [177]
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References 94 · Cited by 132
Research works printed but not linked: 1
- [78]Shi Y Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med 216, 2546– 2561 (2019). 31601677 PMC6829593
- Authors
- Koutsodendris, N., Blumenfeld, J., Agrawal, A., Traglia, M., Grone, B., Zilberter, M., Yip, O., Rao, A., Nelson, M. R., Hao, Y., Thomas, R., Yoon, S. Y., Arriola, P., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Huang, Yadong
- ORCID
- Venue
- Nature Aging
- Published
- 2023-02-20
- Volume
- 3
- Issue
- 3
- Pages
- 275-296
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC10154214
- OpenAlex
- W4321369922
- Cited by
- 132
- References
- 94
- Citations by year
- 2026: 38 · 2025: 43 · 2024: 33 · 2023: 18
- FWCI
- 23.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Aging (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (F31AG074672, R01AG061150, F31AG074690, R01AG071697, P01AG073082)
- 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
- APOE ε4, Alzheimer's disease, tauopathy, tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability, single-nucleus RNA sequencing, oligodendrocytes, astrocytes, microglia
- MeSH terms
- Animals, Gliosis, Myelin Sheath, Neurons, Neurodegenerative Diseases, Tauopathies, Mice, Apolipoprotein E4
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