Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia
Open accessAbstract
The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease and directly influences tauopathy and tau-mediated neurodegeneration. ApoE4 has strong deleterious effects on both parameters. In the brain, apoE is produced and secreted primarily by astrocytes and by activated microglia. The cell-specific role of each form of apoE in the setting of neurodegeneration has not been determined. We generated P301S Tau/Aldh1l1-CreERT2/apoE3 flox/flox or Tau/Aldh1l1-CreERT2/apoE4 flox/flox mice. At 5.5 months of age, after the onset of tau pathology, we administered tamoxifen or vehicle and compared mice at 9.5 months of age. Removing astrocytic APOE4 markedly reduced tau-mediated neurodegeneration and decreased phosphorylated tau (pTau) pathology. Single-nucleus RNA sequencing analysis revealed striking gene expression changes in all cell types, with astrocytic APOE4 removal decreasing disease-associated gene signatures in neurons, oligodendrocytes, astrocytes, and microglia. Removal of astrocytic APOE4 decreased tau-induced synaptic loss and microglial phagocytosis of synaptic elements, suggesting a key role for astrocytic apoE in synaptic degeneration.
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Depletion of astrocytic APOE4 reduces tau levels.
“Depletion of astrocytic APOE4 reduces tau levels [35]”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [35]
The Results section, “Reducing astrocyte-derived apoE4 decreases phosphorylated tau accumulation” (page unavailable), reports reduced pathological phosphorylated tau after astrocytic APOE4 deletion, particularly in female mice. It also reports no significant effect on total human tau in any measured fraction, so the unqualified claim that tau levels fall is too broad. (LLM, conf=0.91)
Experimental — accuracy not yet measuredIn previous studies, the MGnD phenotype was similar between P301S: APOE4-KI and P301S: APOE3-KI mice.
“In previous studies, brain regions of P301S: APOE4 -KI mice demonstrate marked neurodegeneration compared to P301S: APOE3 -KI mice at 9.5 months of age, although the MGnD phenotype was similar between the two groups 12,21 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [12]
The Results section reports a DAM/MGnD microglial shift in both P301S/APOE3 and P301S/APOE4 mice and no major differences in microglial subcluster proportions. However, the Discussion says DAM/MGnD gene-expression elevations were greater with APOE4 than with APOE3, so describing the phenotype as simply similar omits that difference. Page numbers were not available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredOnly astrocytic APOE4 deletion, but not APOE3 deletion, significantly ameliorated tau neurofibrillary tangle burden in tauopathy mice.
“only astrocytic APOE4 deletion, but not APOE3 deletion, significantly ameliorated tau neurofibrillary tangle burden in tauopathy mice149.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [149]
The Results section ('Reducing astrocyte-derived apoE4 decreases phosphorylated tau accumulation'; page unavailable) reports reduced hippocampal AT8 staining after astrocytic APOE4 deletion in female mice, but not male mice or APOE3-deletion mice. It measured phosphorylated-tau deposition rather than neurofibrillary tangle burden directly, and it also found reduced insoluble phosphorylated tau in female APOE3-deletion mice. The claim therefore overgeneralizes both the outcome and the APOE3 comparison. (LLM, conf=0.86)
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 [149]
In the Results section on microglial genes (page unavailable), astrocytic APOE4 removal reduced markers of microglial activation in mice with tau pathology. But the Results section on astrocytes reports fewer activated astrocytes and significantly lower activated-astrocyte gene expression, rather than a largely unchanged response. This paper does not report the claimed effects on responses to Aβ plaques. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE's possible role in Alzheimer's pathophysiology includes cellular mechanisms involving neuronal and glial functions, together with direct effects in Aβ aggregation and deposition.
“APOE’s possible role in Alzheimer’s pathophysiology include cellular mechanisms involving neuronal and glial functions [34, 35], together with direct effects in amyloid-β (Aβ) aggregation and deposition [37].”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [35]
APOE haplotype variants such as APOE4 have been associated with increased risk of sporadic Alzheimer's disease.
“Apolipoprotein E (APOE) haplotype variants such as APOE4 have been associated with increased risk of sporadic Alzheimer’s disease [35].”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [35]
ApoE has a relevant role in AD pathophysiology in astrocytes and immune response to the disease.
“It is known that ApoE has a relevant role in AD pathophysiology in astrocytes and immune response to the disease [35, 36].”
From Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia (2022) · cites this paper as [35]
Deletion of APOE4 in astrocytes markedly reduced neurodegeneration in a mouse model of tauopathy.
“A recent report showed that deletion of APOE4 in astrocytes markedly reduced neurodegeneration in a mouse model of tauopathy 12 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [12]
Neurodegeneration is exacerbated in a mouse model of tauopathy expressing APOE4.
“Neurodegeneration is a pathological hallmark of AD 20 , which is exacerbated in a mouse model of tauopathy expressing APOE4 (refs. 12,21).”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [12]
In previous studies, brain regions of P301S: APOE4-KI mice demonstrate marked neurodegeneration compared to P301S: APOE3-KI mice at 9.5 months of age.
“In previous studies, brain regions of P301S: APOE4 -KI mice demonstrate marked neurodegeneration compared to P301S: APOE3 -KI mice at 9.5 months of age, although the MGnD phenotype was similar between the two groups 12,21 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [12]
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 [149]
Selective removal of astrocytic APOE ε4 strongly protects against tau-induced synaptic loss and reduces microglial-mediated synaptic phagocytosis.
“The role of astrocytic APOE in tau‐mediated neurodegeneration has been highlighted by recent work showing that selective removal of astrocytic APOE ε4 strongly protects against tau‐induced synaptic loss and reduces microglial‐mediated synaptic phagocytosis. 40”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [40]
A recent study shows that selective removal of astrocyte-derived apoE4 (but not apoE3) reduces tau-associated neurodegeneration.
“A recent study shows that selective removal of astrocyte-derived apoE4 (but not apoE3) reduces tau-associated neurodegeneration (Wang et al., 2021).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Wang et al., 2021
Astrocytic apoE4 increases tau-induced synaptic loss and microglia phagocytosis of synaptic elements.
“Studies have documented that astrocytic apoE4 increases tau-induced synaptic loss and microglia phagocytosis of synaptic elements [48]”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [48]
Deletion of astrocytic ApoE4 markedly reduces phosphorylated tau.
“Deletion of astrocytic ApoE4 markedly reduces phosphorylated tau [142].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [142]
Selective removal of astrocytic APOE4 decreases microglial phagocytosis of synaptic elements in the tau transgenic mouse model.
“Selective removal of astrocytic APOE4 decreased microglial phagocytosis of synaptic elements in the tau transgenic mouse model.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [96]
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Self-citationAPOE4 derived from astrocytes leads to blood–brain barrier impairment
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- Authors
- Wang, C., Xiong, M., Gratuze, M., Bao, X., Shi, Y., Andhey, P. S., Manis, M., Schroeder, C., Yin, Z., Madore, C., Butovsky, O., Artyomov, M., Ulrich, J. D., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Ulrich, Jason D.
- Holtzman, David M.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 109
- Issue
- 10
- Pages
- 1657-1674.e7
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8141024
- OpenAlex
- W3146687755
- Cited by
- 334
- References
- 74
- Citations by year
- 2026: 48 · 2025: 69 · 2024: 59 · 2023: 81 · 2022: 60 · 2021: 16
- FWCI
- 33.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- National Institutes of Health
- JPB Foundation
- Cure Alzheimer's Fund
- 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, APOE ε4, astrocytes, tauopathy, Alzheimer's disease, microglial phagocytosis, synaptic loss, phosphorylated tau, single-nucleus RNA sequencing, cell type-specific gene expression, P301S tau
- MeSH terms
- Animals, Astrocytes, Humans, Mice, Inbred C57BL, Phagocytosis, Synapses, tau Proteins, Apoptosis, Microglia, Tauopathies, Mice, Apolipoprotein E4, Transcriptome
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