Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-β plaque formation in organotypic hippocampal slice cultures
Open accessAbstract
The role of microglia in amyloid-β (Aβ) deposition is controversial. In the present study, an organotypic hippocampal slice culture (OHSC) system with an in vivo-like microglial-neuronal environment was used to investigate the potential contribution of microglia to Aβ plaque formation. We found that microglia ingested Aβ, thereby preventing plaque formation in OHSCs. Conversely, Aβ deposits formed rapidly in microglia-free wild-type slices. The capacity to prevent Aβ plaque formation was absent in forebrain microglia from young adult but not juvenile 5xFamilial Alzheimer’s disease (FAD) mice. Since no loss of Aβ clearance capacity was observed in both wild-type and cerebellar microglia from 5xFAD animals, the high Aβ 1−42 burden in the forebrain of 5xFAD animals likely underlies the exhaustion of microglial Aβ clearance capacity. These data may therefore explain why Aβ plaque formation has never been described in wild-type mice and point to a beneficial role of microglia in AD pathology. We also describe a new method to study Aβ plaque formation in a cell culture setting.
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Microglia play a crucial role in clearing Aβ plaques in the brain during Alzheimer's disease progression.
“Microglia play a crucial role in clearing Aβ plaques in the brain during AD progression (25, 26).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [26]
The Results section reports that microglia ingest and digest Aβ in organotypic hippocampal slice cultures, and the Discussion describes a beneficial role in clearing Aβ. The paper supports a role in limiting plaque formation in that model, but does not establish that microglia clear existing plaques in the brain during AD progression; its Abstract notes that microglial depletion did not affect plaque load in two in vivo mouse models. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRapid pruning of damaged synapses near dystrophic neurites localized around plaques appears to be, at least initially, protective and may go awry later in disease progression.
“Rapid pruning of damaged synapses near dystrophic neurites localized around plaques appears to be, at least initially, protective and may go awry later in disease progression as described before68.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [68]
The Discussion (page unavailable) says microglia from young 5xFAD mice can initially prevent plaque formation, whereas those from older mice lose that ability. It attributes this protective effect to amyloid-β clearance, not rapid pruning of damaged synapses near plaque-associated dystrophic neurites; the specific mechanism in the claim is unsupported. (LLM, conf=0.78)
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Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · see citing works
Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543 · see citing works
Karran, E., Mercken, M., & Strooper, B. D. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3505 · Cited by 2,188 · see citing works
Elmore, M. R. P., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E., Rice, R. A., Kitazawa, M., Matusow, B., Nguyen, H., West, B. L., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.040 · Cited by 1,968 · see citing works
Self-propagation of pathogenic protein aggregates in neurodegenerative diseases
Jucker, M., & Walker, L. C. (2013) · Nature · doi:10.1038/nature12481 · Cited by 1,663 · see citing works
Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways
Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E. G., Wieghofer, P., Heinrich, A., Riemke, P., Hölscher, C., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3318 · Cited by 1,457 · see citing works
Self-citationExogenous Induction of Cerebral ß-Amyloidogenesis Is Governed by Agent and Host
Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., Neuenschwander, A., Abramowski, D., Frey, P., Jaton, A. L., et al. (2006) · Science · doi:10.1126/science.1131864 · Cited by 971 · see citing works
Self-citationWebster, S. J., Bachstetter, A. D., Nelson, P. T., Schmitt, F. A., & Van Eldik, L. J. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00088 · Cited by 755 · see citing works
Krabbe, G., Halle, A., Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., Miller, K. R., Prokop, S., Kettenmann, H., & Heppner, F. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060921 · Cited by 478 · see citing works
Neuroinflammatory processes in Alzheimer’s disease
Heneka, M. T., O’Banion, M. K., Terwel, D., & Kummer, M. P. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0438-z · Cited by 433 · see citing works
Formation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia
Grathwohl, S. A., Kälin, R. E., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., Odenthal, J., Radde, R., Eldh, T., Gandy, S., et al. (2009) · Nature Neuroscience · doi:10.1038/nn.2432 · Cited by 401 · see citing works
D'Andrea, M. R., Nagele, R. G., Wang, H., Peterson, P. A., & Lee, D. H. S. (2001) · Histopathology · doi:10.1046/j.1365-2559.2001.01082.x · Cited by 390 · see citing works
Lucin, K. M., O’Brien, C. E., Bieri, G., Czirr, E., Mosher, K. I., Abbey, R. J., Mastroeni, D. F., Rogers, J., Spencer, B., Masliah, E., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.046 · Cited by 374 · see citing works
Neuroprotective function for ramified microglia in hippocampal excitotoxicity
Vinet, J., van Weering, H. R., Heinrich, A., Kälin, R. E., Wegner, A., Brouwer, N., Heppner, F. L., van Rooijen, N., Boddeke, H. W., & Biber, K. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-27 · Cited by 274 · see citing works
Self-citationTREM2 and the neuroimmunology of Alzheimer's disease
Hickman, S. E., & El Khoury, J. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.11.021 · Cited by 221 · see citing works
The brain’s best friend: microglial neurotoxicity revisited
Hellwig, S., Heinrich, A., & Biber, K. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00071 · Cited by 126 · see citing works
Flagged first, then by citations
Research works printed but not linked: 29
- Gilbert B. J. The role of amyloid β in the pathogenesis of Alzheimer’s disease. J. Clin. Pathol. 66, 362– 366 (2013). 23526599
- Malm T. M., Jay T. R. & Landreth G. E. The Evolving Biology of Microglia in Alzheimer’s Disease. Neurother. J. Am. Soc. Exp. Neurother. (2014). doi: 10.1007/s13311-014-0316-8. PMC4322081 25404051 · DOI · Paper page
- Prokop S., Miller K. R. & Heppner F. L. Microglia actions in Alzheimer’s disease. Acta Neuropathol. (Berl.) 126, 461– 477 (2013). 24224195
- Fleisher-Berkovich S. et al. Distinct modulation of microglial amyloid β phagocytosis and migration by neuropeptides (i). J. Neuroinflammation 7, 61 (2010). 20937084 PMC2964654
- Fu H. et al. Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia. Glia 60, 993– 1003 (2012). 22438044 PMC3325361
- Griciuc A. et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631– 643 (2013). 23623698 PMC3706457
- Mandrekar S. et al. Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J. Neurosci. Off. J. Soc. Neurosci. 29, 4252– 4262 (2009). PMC3034143 19339619
- Beutner C. et al. Engineered stem cell-derived microglia as therapeutic vehicle for experimental autoimmune encephalomyelitis. Gene Ther. 20, 797– 806 (2013). 23324824
- Biber K., Owens T. & Boddeke E. What is microglia neurotoxicity (Not)? Glia 62, 841– 854 (2014). 24590682
- Hickman S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896– 1905 (2013). 24162652 PMC3840123
- Varvel N. H. et al. Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc. Natl. Acad. Sci. USA 109, 18150– 18155 (2012). 23071306 PMC3497743
- Bahr B. A. Long-term hippocampal slices: a model system for investigating synaptic mechanisms and pathologic processes. J. Neurosci. Res. 42, 294– 305 (1995). 8583497
- Stoppini L., Buchs P. A. & Muller D. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173– 182 (1991). 1715499
- Mewes A., Franke H. & Singer D. Organotypic brain slice cultures of adult transgenic P301S mice–a model for tauopathy studies. PloS One 7, e45017 (2012). 22984603 PMC3439393
- Braithwaite S. P. et al. Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer’s disease. Neurobiol. Dis. 39, 311– 317 (2010). 20451607 PMC2910136
- Alberdi E. et al. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 47, 264– 272 (2010). 20061018
- Kane M. D. et al. Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice. J. Neurosci. Off. J. Soc. Neurosci. 20, 3606– 3611 (2000). PMC6772682 10804202
- Ji K., Akgul G., Wollmuth L. P. & Tsirka S. E. Microglia actively regulate the number of functional synapses. PloS One 8, e56293 (2013). 23393609 PMC3564799
- Sturchler-Pierrat C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. USA 94, 13287– 13292 (1997). 9371838 PMC24301
- Radde R. et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7, 940– 946 (2006). 16906128 PMC1559665
- Lee J.-H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146– 1158 (2010). 20541250 PMC3647462
- Pickford F. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest. 118, 2190– 2199 (2008). 18497889 PMC2391284
- Orre M. et al. Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol. Aging 35, 2746– 2760 (2014). 25002035
- Mosher K. I. & Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol. 88, 594– 604 (2014). 24445162 PMC3972294
- De Jong E. K. et al. Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3. J. Neurochem. 105, 1726– 1736 (2008). 18248618
- De Haas A. H., Boddeke H. W. G. M., Brouwer N. & Biber K. Optimized isolation enables ex vivo analysis of microglia from various central nervous system regions. Glia 55, 1374– 1384 (2007). 17661344
- De Haas A. H., Boddeke H. W. G. M. & Biber K. Region-specific expression of immunoregulatory proteins on microglia in the healthy CNS. Glia 56, 888– 894 (2008). 18338796
- Van Weering H. R. J. et al. CXCL10/CXCR3 signaling in glia cells differentially affects NMDA-induced cell death in CA and DG neurons of the mouse hippocampus. Hippocampus 21, 220– 232 (2011). 20082289
- Sun A., Nguyen X. V. & Bing G. Comparative analysis of an improved thioflavin-s stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections. J. Histochem. Cytochem. Off. J. Histochem. Soc. 50, 463– 472 (2002). 11897799
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Self-citation
- Authors
- Hellwig, S., Masuch, A., Nestel, S., Katzmarski, N., Meyer-Luehmann, M., & Biber, K.
- Affiliations
- University of Freiburg (DE)
- University Medical Center Groningen (NL)
- Corresponding author
- Biber, Knut
- Venue
- Scientific Reports
- Published
- 2015-09-29
- Volume
- 5
- Issue
- 1
- Pages
- 14624-14624
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4586757
- OpenAlex
- W2397672509
- Cited by
- 91
- References
- 16
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 4 · 2023: 9 · 2022: 6 · 2021: 11 · 2020: 11 · 2019: 14 · 2018: 4 · 2017: 10 · 2016: 12
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (FOR1336)
- Bundesministerium für Bildung und Forschung
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglia, amyloid-beta, Alzheimer's disease, 5xFAD mice, organotypic hippocampal slice cultures, microglial phagocytosis, amyloid-beta clearance, amyloid-beta 42
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Biological Transport, Disease Models, Animal, Female, Hippocampus, Male, Mice, Inbred C57BL, Mice, Transgenic, Microtomy, Peptide Fragments, Amyloid beta-Peptides, Prosencephalon, Microglia, Tissue Culture Techniques, Mice, Plaque, Amyloid, Disease Resistance
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