Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis
Open accessAbstract
Background: One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, it is not fully known how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology. Methods: We utilized APOE knock-in mice capable of having APOE selectively removed from astrocytes in a tamoxifen-inducible manner and crossed them with the APP/PS1-21 mouse model of amyloidosis. We analyzed the changes to Aβ plaque levels and assessed the impact on cellular responses to Aβ plaques when astrocytic APOE is removed. Results: Tamoxifen administration was capable of strongly reducing apoE levels in the brain by markedly reducing astrocyte apoE, while microglial apoE expression remained. Reduction of astrocytic apoE3 and apoE4 led to a large decrease in Aβ plaque deposition and less compact plaques. While overall Iba1+ microglia were unchanged in the cortex after reducing astrocyte apoE, the expression of the disease-associated microglial markers Clec7a and apoE were lower around amyloid plaques, indicating decreased microglial activation. Additionally, astrocyte GFAP levels are unchanged around amyloid plaques, but overall GFAP levels are reduced in the cortex of female apoE4 mice after a reduction in astrocytic apoE. Finally, while the amount of neuritic dystrophy around remaining individual plaques was increased with the removal of astrocytic apoE, the overall amount of cortical amyloid-associated neuritic dystrophy was significantly decreased. Conclusion: This study reveals an important role of astrocytic apoE3 and apoE4 on the deposition and accumulation of Aβ plaques as well as on certain Aβ-associated downstream effects.
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Removal of both astrocytic APOE3 and APOE4 is protective against Aβ deposition in plaque-depositing mice, lowering plaque burden to the levels of Apoe knockout mice.
“removal of both astrocytic APOE3 and APOE4 is protective against Aβ deposition in plaque-depositing mice; specifically, plaque burden was lowered to the levels of Apoe knockout mice148.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [148]
The Results (Aβ plaque accumulation in mice lacking astrocytic APOE; page unavailable) report reduced fibrillar plaque burden after astrocytic apoE3 or apoE4 removal, with total fibrillar amyloid burden qualitatively similar to that in Apoe-knockout mice. But the same section reports no significant reduction in male APOE3 mice and a qualitatively higher overall Aβ plaque load in knockout mice. Thus, the claim overgeneralizes the reduction and the comparison with knockout levels. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRemoval of astrocytic APOE reduced microglial reaction to Aβ plaques and neurofibrillary tangles, but astrocyte response to plaques and tangles was largely unchanged.
“removal of astrocytic APOE reduced microglial reaction to Aβ plaques and neurofibrillary tangles, but that astrocyte response to plaques and tangles was largely unchanged148,149”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [148]
The Discussion reports lower microglial activation around Aβ plaques after astrocytic apoE reduction, and the Results (Astrocyte activation after the loss of astrocytic apoE) report unchanged GFAP staining around plaques. The paper’s findings concern Aβ plaques, not neurofibrillary tangles; it does not support either claimed response to tangles. Page numbers were not supplied in our copy. (LLM, conf=0.91)
Experimental — accuracy not yet measuredRestoration of APOE expression in astrocytes alone is sufficient to induce formation of fibrillar plaques and microglia reactivity.
“Restoration of APOE expression in astrocytes alone is sufficient to induce formation of fibrillar plaques and microglia reactivity, extending findings from previous studies (Holtzman et al, 2000a; Liu et al, 2017b; Mahan et al, 2022).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Mahan et al, 2022
The Discussion (page unavailable) reports that removing astrocytic apoE strongly reduced fibrillar plaques, and the Results section on microglial activation (page unavailable) reports reduced activation-associated gene expression after that removal. These findings support a role for astrocytic apoE in both outcomes, but the paper tested reduction, not restoration of APOE expression in astrocytes alone; it therefore does not establish the claimed sufficiency. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFindings from Mahan et al. suggested a role for astrocyte-derived ApoE in amyloid reduction and associated gliosis.
“findings from a study by Mahan et al.36 suggested a role for astrocyte-derived ApoE in amyloid reduction and associated gliosis.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as Mahan et al.36
Mahan et al. observed a decrease in reactive microglia using Clec7a and a reduction in plaque-associated ApoE, but did not report decreases in IBA1 as seen in this study.
“While that study did not report decreases in IBA1 as those seen in this study, they observed a similar decrease in reactive microglia using Clec7a, and a reduction in plaque-associated ApoE.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as Mahan et al.36
Microglia are affected by astrocytic APOE.
“the characterization of microglia in astrocyte-specific Apoe knockout mice certainly indicates that microglia are affected by astrocytic APOE148,149.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [148]
Astrocyte-specific deletion of APOE reduces amyloid pathology and associated toxicity.
“reports of astrocyte-specific deletion of APOE reducing amyloid pathology and associated toxicity [19].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [19]
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 [176]
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- Authors
- Mahan, T. E., Wang, C., Bao, X., Choudhury, A., Ulrich, J. D., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Holtzman, David M.
- Venue
- Molecular Neurodegeneration
- Published
- 2022-02-02
- Volume
- 17
- Issue
- 1
- Pages
- 13-13
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC8811969
- OpenAlex
- W4210382695
- Cited by
- 134
- References
- 87
- Citations by year
- 2026: 19 · 2025: 35 · 2024: 31 · 2023: 29 · 2022: 20
- FWCI
- 17.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- cure alzheimer's fund
- jpb foundation
- national institute of neurological disorders and stroke (NS090932)
- national institute on aging (AG047644)
- 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
- apolipoprotein E, astrocytes, APOE3, APOE ε4, amyloid-beta, amyloid plaques, Alzheimer's disease, APP/PS1 mice, microglial activation, Dectin-1, glial fibrillary acidic protein, neuritic dystrophy
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Astrocytes, Female, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid
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