Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease
Open accessAbstract
Microglia are known as resident immune cells in the brain. β-amyloid (Aβ) plaques in the brain of Alzheimer’s disease (AD) are surrounded by microglia, but whether and how microglia affect the formation and maintenance of plaques remains controversial. We depleted microglia by injecting diphtheria toxin (DT) in CX 3 CR1 CreER/+ :R26 DTR/+ (CX 3 CR1-iDTR) mice crossed with APPswe/PSEN1dE9 (APP/PS1) mice. Intravital time-lapse imaging was performed to examine changes in the number and size of Congo Red-labeled amyloid plaques over 1–2 weeks. We also examined spine density and shaft diameter of dendrites passing through plaques in a PSAPP mouse model of AD (PS1 M146L line 6.2 × Tg2576) crossed with Thy1 YFP H-line mice. We found that DT administration to CX 3 CR1-iDTR mice efficiently ablated microglia within one week and that microglia repopulated in the second week after DT administration. Microglia depletion didn’t affect the number of amyloid plaques, but led to ~13% increase in the size of Aβ plaques within one week. Moreover, microglia repopulation was associated with the stabilization of plaque size during the second week. In addition, we found dendritic spine loss and shaft atrophy in the distal parts of dendrites passing through plaques. Our results demonstrate the important role of microglia in limiting the growth of Aβ plaques and plaque-associated disruption of neuronal connection.
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Efficient microglial clustering around plaques is essential for Aβ clearance and restricting local Aβ toxicity.
“Because ef fi cient microglial clustering around plaques is essential for A β clearance and restricting local A β toxicity 25,26 , we next assessed plaque-microglia interactions by co-staining Iba1 with X-34.”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [26]
The Background (page not available) describes microglia clustered around plaques and reports evidence linking them to Aβ clearance and a barrier against plaque expansion. The Discussion (page not available) reports that microglia depletion enlarged plaques and suggests a role in limiting neuronal damage. It does not establish that efficient clustering is essential for Aβ clearance or for restricting local Aβ toxicity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia form stable, protective barriers around Aβ plaques and compact Aβ into tightly packed, less toxic forms.
“Microglia are deployed to form stable, protective barriers around Aβ plaques in the AD brain, and work to compact Aβ into tightly packed, less toxic forms (Casali et al., 2020; Condello et al., 2015; Zhao et al., 2017).”
From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Zhao et al., 2017
The Background says microglial processes envelop plaques and may form a barrier that prevents expansion; the Conclusion reports that microglia limit plaque growth in a mouse model. Our copy does not establish that the barriers are stable or that microglia compact Aβ into tightly packed, less toxic forms. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia can use their highly dynamic and mobile processes to compact Aβ fibrils into tightly packed aggregates, reducing Aβ aggregate surface area and limiting their potential neurotoxic effects on nearby neurons.
“They can also use their highly dynamic and mobile processes to compact Aβ fibrils into tightly packed aggregates, reducing Aβ aggregate surface area and thereby limiting their potential neurotoxic effects on nearby neurons (Casali et al., 2020; Condello et al., 2015; Zhao et al., 2017).”
From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Zhao et al., 2017
The Background (page unavailable) describes microglial processes enveloping plaques as a possible barrier to expansion, and the Conclusion (page unavailable) says microglia limit plaque growth and associated neuronal damage. But the paper does not establish the claimed mechanism of dynamic processes compacting Aβ fibrils into tightly packed aggregates, reducing their surface area, and thereby reducing toxicity. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn human AD and mouse models, microglia surround Aβ plaques.
“Both in human AD and its mouse models, microglia surround Aβ plaques [216, 226, 365]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [365]
The degree of plaque compaction positively correlates with neuronal health.
“These protective functions of microglia have been shown to limit axonal dystrophy to neurons in the immediate area, with the degree of plaque compaction positively correlating with neuronal health (Casali et al., 2020; Condello et al., 2015; Zhao et al., 2017).”
From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Zhao et al., 2017
The Results and Discussion passages report that microglia restrict plaque enlargement and that dendrites passing through plaques show abnormalities, including beyond the immediate plaque area. A search for plaque compaction found no passage measuring its degree or correlating it with neuronal health, so the attributed correlation cannot be verified from this paper. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Plaque size increased ∼13% over 1 wk in microglia-depleted brains.
“a study that used time-lapse imaging to track individual plaques in vivo reported that plaque size increased ∼13% over 1 wk in microglia-depleted brains (Zhao et al., 2017).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Zhao et al., 2017
Pro-inflammatory microglia are closely associated with protein aggregate pathologies characteristic of most dementias.
“Immune involvement in neurodegenerative disease centres on findings that pro-inflammatory microglia are closely associated with protein aggregate pathologies characteristic of most dementias.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [14]
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References 54 · Cited by 151
- Authors
- Zhao, R., Hu, W., Tsai, J., Li, W., & Gan, W.-B.
- Affiliations
- Peking University (CN)
- New York University (US)
- Corresponding author
- Li, Wei
- Gan, Wen-Biao
- Venue
- Molecular Neurodegeneration
- Published
- 2017-06-12
- Volume
- 12
- Issue
- 1
- Pages
- 47-47
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC5468952
- OpenAlex
- W2625911761
- Cited by
- 151
- References
- 54
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 15 · 2023: 25 · 2022: 24 · 2021: 21 · 2020: 15 · 2019: 10 · 2018: 12 · 2017: 2
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (5R01 NS087198)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglia, amyloid plaques, Alzheimer's disease, microglial depletion, diphtheria toxin, plaque size, microglial repopulation, dendritic spine loss, APP/PS1 mice, Tg2576 mice
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Plaque, Amyloid, Time-Lapse Imaging
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