Formation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia
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In Alzheimer's disease, microglia cluster around beta-amyloid deposits, suggesting that these cells are important for amyloid plaque formation, maintenance and/or clearance. We crossed two distinct APP transgenic mouse strains with CD11b-HSVTK mice, in which nearly complete ablation of microglia was achieved for up to 4 weeks after ganciclovir application. Neither amyloid plaque formation and maintenance nor amyloid-associated neuritic dystrophy depended on the presence of microglia.
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It remains unclear to what extent microglia are capable of removing amyloid from pre-existing fibrillar congophilic plaques or of preventing the deposition of smaller protofibrillar Aβ aggregates.
“it remains unclear to what extent microglia are capable of removing amyloid from pre-existing fibrillar congophilic plaques (Stalder et al., 2001) or of preventing the deposition of smaller protofibrillar Aβ aggregates (Grathwohl et al., 2009).”
From CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis (2010) · cites this paper as Grathwohl et al., 2009
The citation to Grathwohl et al. attaches to the claim about preventing deposition of smaller protofibrillar Aβ aggregates, not to the preceding claim about removing pre-existing plaques. In the Introduction (page unavailable), the paper reports that microglial ablation did not prevent plaque formation or change the extent of Aβ deposition in APP mouse models. It does not specifically assess smaller protofibrillar aggregates, so it supports the broader uncertainty about microglia and deposition but not that specific form. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGancyclovir-mediated depletion of microglia expressing thymidine kinase had no demonstrable effect on Aβ pathology in two mouse models of AD.
“Finally, a recent study provided evidence that gancyclovir-mediated depletion of microglia expressing thymidine kinase had no demonstrable effect on A pathology in two mouse models of AD. 57”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [57]
The Introduction reports no change in Aβ deposition or plaques after microglial depletion in APPPS1 mice. In the second model, APP23, it reports unchanged congophilic and vascular amyloid but a small reduction in total Aβ load, mainly from reduced diffuse amyloid. Thus, 'no demonstrable effect on Aβ pathology' overstates the result across both models. Page numbers are not provided in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPrevious in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid to suggesting that microglia play no role in the control of amyloid deposition.
“Previous in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid (Frautschy et al., 1991; Bacskai et al., 2002; Bolmont et al., 2008) to suggesting that microglia play no role in the control of amyloid deposition (Grathwohl et al., 2009).”
From CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis (2010) · cites this paper as Grathwohl et al., 2009
The formation and maintenance of β-amyloid plaques in amyloidosis models does not seem to be affected by CSF1R inhibition or other methods of microglia depletion.
“Unlike with synapse loss, the formation and maintenance of β-amyloid plaques in amyloidosis models does not seem to be affected by CSF1R inhibition or other methods of microglia depletion (Grathwohl et al., 2009; Olmos-Alonso et al., 2016; Spangenberg et al., 2016).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Grathwohl et al., 2009
Aβ clearance and plaque modulation/dynamics is unaffected following microglia surround plaques.
“Despite this response, however, Aβ clearance and plaque modulation/dynamics is unaffected10–12”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [11]
Depleting microglia after amyloid-β pathology onset via pharmacological inhibition of CSF1R signalling or by using the CD11b-HSVTK system for 4 weeks does not affect total plaque burden.
“depleting microglia after amyloid-β pathology onset via pharmacological inhibition of colony-stimulating factor 1 receptor (CSF1R) signalling38 or by using the CD11b-HSVTK (TK) system39 for 4 weeks, does not affect total plaque burden.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [39]
Data examining the effects of microglia and inflammatory mediators on Aβ deposition in APP transgenic mice are mixed, with some studies showing reduced and others exacerbated Aβ accumulation.
“Similarly, data examining the effects of microglia and inflammatory mediators on Aβ deposition in APP transgenic mice are mixed, with some studies demonstrating reduced and others exacerbated Aβ accumulation [120–122].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [122]
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- Authors
- Grathwohl, S. A., Kälin, R. E., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., Odenthal, J., Radde, R., Eldh, T., Gandy, S., Aguzzi, A., Staufenbiel, M., Mathews, P. M., Wolburg, H., Heppner, F. L., & Jucker, M.
- Affiliations
- Hertie Institute for Clinical Brain Research (DE)
- Charité – Universitätsmedizin Berlin (DE)
- German Center for Neurodegenerative Diseases (DE)
- University of Tübingen (DE)
- Icahn School of Medicine at Mount Sinai (US)
- University Hospital Zurich (CH)
- Novartis (Switzerland) (CH)
- Nathan Kline Institute for Psychiatric Research (US)
- Corresponding author
- Heppner, Frank L
- Jucker, Mathias
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2009-10-18
- Volume
- 12
- Issue
- 11
- Pages
- 1361-1363
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4721582
- OpenAlex
- W2066165659
- Cited by
- 401
- References
- 22
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 11 · 2023: 19 · 2022: 8 · 2021: 27 · 2020: 20 · 2019: 21 · 2018: 26 · 2017: 33 · 2016: 21 · 2015: 38 · 2014: 27 · 2013: 33 · 2012: 43
- FWCI
- 22.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institute on Aging (P01AG010491, AG017617, P01AG017617)
- National Institute of Neurological Disorders and Stroke (NS045205, R01NS045205, R01NS046006)
- 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
- Alzheimer's disease, amyloid plaques, microglia, ganciclovir, APP transgenic mice, neuritic dystrophy, plaque clearance, mouse models of Alzheimer's disease
- MeSH terms
- CD68 Molecule, Alzheimer Disease, Animals, Antiviral Agents, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Regulation, Humans, Injections, Intra-Articular, Male, Mice, Transgenic, Mutation, Plague, Thymidine Kinase, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Ganciclovir, Amyloid beta-Peptides, Microscopy, Immunoelectron, Amyloid beta-Protein Precursor, Microglia, Neuroaxonal Dystrophies, CD11b Antigen, Green Fluorescent Proteins, Mice, Presenilin-1
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