Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model
Open accessAbstract
Chronic activation of brain innate immunity is a prominent feature of Alzheimer’s disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of ptau pathology is also driven by microglia. In addition, we found that APOE, the strongest genetic risk factor for AD, regulates neurodegeneration predominantly by modulating microglial activation, although a minor role of apoE in regulating ptau and insoluble tau formation independent of its immunomodulatory function was also identified. Our results suggest that therapeutic strategies targeting microglia may represent an effective approach to prevent disease progression in the setting of tauopathy.
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APOE4 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 [11]
The Introduction says apoE4 significantly exacerbated neurodegeneration in P301S tauopathy mice. The Results link apoE to phosphorylated-tau pathology and show greater microglial activation in apoE4 mice than in apoE-deficient mice. The paper does not show that APOE4 exacerbates amyloid-β plaques, and its tau findings concern tau pathology rather than specifically demonstrating more tangles. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMounting evidence shows that APOE downstream effects converge on the microglial response to protein aggregates.
“Indeed, mounting evidence shows that APOE downstream effects converge on the microglial response to protein aggregates, as further discussed subsequently129,130.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [130]
The Discussion reports that apoE’s effects on tau pathology and neurodegeneration in a tauopathy mouse model were mediated predominantly through microglial function. The Introduction identifies tau as an aggregated protein, but the paper’s finding does not establish convergence of APOE effects on microglial responses to protein aggregates generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredStudies using transgenic P301STau mice report that microglial depletion reduced neurodegeneration and the accumulation of phosphorylated tau.
“In line with our findings, studies using transgenic P301STau mice report that microglial depletion reduced neurodegeneration and the accumulation of phosphorylated tau (Johnson et al., 2023; Mancuso et al., 2019; Shi et al., 2019).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Shi et al., 2019
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 [11]
Microglia are the principal driving force of neurodegeneration and tau pathogenesis in tauopathy mouse models.
“We and others subsequently identified microglia as the principal driving force of neurodegeneration and tau pathogenesis in tauopathy mouse models (Mancuso et al., 2019; Shi et al., 2019).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Shi et al., 2019
Microglial depletion in P301S mice fully blocked neurodegeneration and stopped tau pathology progression.
“Microglial depletion in P301S mice fully blocked neurodegeneration and stopped tau pathology progression.”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Shi et al., 2019
ApoE promotes neurodegeneration and tau pathogenesis predominantly by driving microglial activation.
“ApoE had a strong immunomodulatory function and promoted neurodegeneration and tau pathogenesis predominantly by driving microglial activation (Shi et al., 2019).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Shi et al., 2019
No significant difference in AT8+ area coverage was observed between PS19 and PS19;ApoeCh mice at both 5 and 9 mo of age.
“However, no significant difference was observed between PS19 and PS19;ApoeCh mice at both 5 and 9 mo of age (Fig. 5a-d, Supp. Figure 14a-c) [45, 67–69].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [68]
The Animals section describes P301S mice crossed with APOE4 knock-in or Apoe knockout mice, not ApoeCh mice. Results (Fig. 4; page unavailable) quantify AT8-covered area in 9.5-month-old TE4 and TEKO mice, but do not report a PS19 versus PS19;ApoeCh comparison at 5 or 9 months. Searches for ApoeCh and the stated age-specific AT8 comparison found no supporting passage in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredAPOE4 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 [174]
The microglial response to amyloid plaques and/or tau pathology is increasingly thought to cause or contribute heavily to disease-related neurodegeneration.
“the microglial response to amyloid plaques and/or tau pathology is increasingly thought to cause or contribute heavily to disease-related neurodegeneration [10], [11], [12], [13].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [11]
APOE may regulate neurodegeneration in a TREM2-mediated fashion.
“emerging evidence suggests that APOE, a potent immune modulator and strongest of genetic risk factors for LOAD [113–115], may regulate neurodegeneration in a TREM2-mediated fashion [116, 117].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [116]
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Stancu, I. C., Lodder, C., Botella Lucena, P., Vanherle, S., Gutiérrez de Ravé, M., Terwel, D., Bottelbergs, A., & Dewachter, I. (2022) · Glia · doi:10.1002/glia.24160 · Cited by 72 · see citing works
Microglia: Friend and foe in tauopathy
Odfalk, K. F., Bieniek, K. F., & Hopp, S. C. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102306 · Cited by 60 · see citing works
Tau-targeting therapy in Alzheimer’s disease: Critical advances and future opportunities
Guo, Y., Li, S., Zeng, L.-H., & Tan, J. (2022) · Ageing and Neurodegenerative Diseases · doi:10.20517/and.2022.16 · Cited by 61 · see citing works
McFarland, K. N., & Chakrabarty, P. (2022) · Neurotherapeutics · doi:10.1007/s13311-021-01179-3 · Cited by 48 · see citing works
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A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation
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“In line with our findings, studies using transgenic P301STau mice report that microglial depletion reduced neurodegeneration and the accumulation of phosphorylated tau (Johnson et al., 2023; Mancuso et al., 2019; Shi et al., 2019).”
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Current insights into apolipoprotein E and the immune response in Alzheimer's disease
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Non-invasive in vivo imaging of brain and retinal microglia in neurodegenerative diseases
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ApoE expression across the CNS: Who, What, Where, When, and How (much)?
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- Authors
- Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P. M., Remolina Serrano, J., Hoyle, R., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Duke University (US)
- Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 1
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2019-10-10
- Volume
- 216
- Issue
- 11
- Pages
- 2546-2561
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC6829593
- OpenAlex
- W2980270906
- Cited by
- 448
- References
- 26
- Citations by year
- 2026: 44 · 2025: 51 · 2024: 76 · 2023: 98 · 2022: 74 · 2021: 51 · 2020: 51 · 2019: 2 · 2014: 1
- FWCI
- 30.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health (NS090934, AG047644)
- JPB Foundation
- Cure Alzheimer’s Fund
- Washington University School of Medicine
- Children’s Discovery Institute (CDI-CORE-2015-505)
- Foundation for Barnes-Jewish Hospital (3770)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, apolipoprotein E, tauopathy, neurodegeneration, Alzheimer's disease, microglial activation, phosphorylated tau, microglia-targeted therapy, mouse model
- MeSH terms
- Alzheimer Disease, Aminopyridines, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Humans, Mice, Inbred C57BL, Mice, Transgenic, Pyrroles, tau Proteins, Microglia, Mice, Knockout, Dietary Supplements, Neurodegenerative Diseases, Tauopathies
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