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Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology
Open accessAbstract
In addition to amyloid-β plaque and tau neurofibrillary tangle deposition, neuroinflammation is considered a key feature of Alzheimer’s disease pathology. Inflammation in Alzheimer's disease is characterized by the presence of reactive astrocytes and activated microglia surrounding amyloid plaques, implicating their role in disease pathogenesis. Microglia in the healthy adult mouse depend on colony-stimulating factor 1 receptor (CSF1R) signalling for survival, and pharmacological inhibition of this receptor results in rapid elimination of nearly all of the microglia in the central nervous system. In this study, we set out to determine if chronically activated microglia in the Alzheimer's disease brain are also dependent on CSF1R signalling, and if so, how these cells contribute to disease pathogenesis. Ten-month-old 5xfAD mice were treated with a selective CSF1R inhibitor for 1 month, resulting in the elimination of ∼80% of microglia. Chronic microglial elimination does not alter amyloid-β levels or plaque load; however, it does rescue dendritic spine loss and prevent neuronal loss in 5xfAD mice, as well as reduce overall neuroinflammation. Importantly, behavioural testing revealed improvements in contextual memory. Collectively, these results demonstrate that microglia contribute to neuronal loss, as well as memory impairments in 5xfAD mice, but do not mediate or protect from amyloid pathology. Microglia-mediated inflammation is a driving force in Alzheimer’s disease pathogenesis. Spangenberg et al . show that elimination of microglia in 5xfAD mice improves cognitive function and ameliorates synaptic/neuronal loss without altering amyloid-β levels or plaque load. Thus, microglia act downstream of plaques to mediate damage to the brain.
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“In mice that serve as a model for Alzheimer’s disease, microglia depletion was generally beneficial by decreasing plaque formation (26).”
From Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection (2020) · cites this paper as [26]
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Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In mouse models of AD genetic or pharmacological depletion of microglia prevented microglia association with amyloid plaques and neuronal loss, which led to improved learning and memory without affecting amyloid plaque load in mouse brain (Dagher et al., 2015; Rice et al., 2015; Spangenberg et al., 2016).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Spangenberg et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“microglia depletion before or after the formation of Aβ pathology in mouse models of AD resulted in improved contextual memory”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [296]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“While the use of these agents is limited in experimental TBI studies, several groups have reported that microglial elimination [via colony-stimulating factor 1 receptor (CSF1R) inhibition] improves behavioral performance and synaptic functioning independent of Aβ accumulation in multiple transgenic mouse models of AD (3xTg, 5xFAD, APP/PS1) (236–238).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [236]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Ablation of microglia in younger mice before development of cerebral amyloidosis thus reduces Aβ deposition [294], while ablation of microglia later in disease (i.e., in 10-month-old 5xFAD mice) [296], does not alter Aβ load.”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [296]
The cited source says what the claim attributes to it.
In the citing paper
“suggesting that these cells are dispensable for Aβ clearance and plaque formation in the late stage of disease [296]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [296]
The cited source says what the claim attributes to it.
In the citing paper
“microglia ablation in AD mouse models at 10 months of age had no impact on plaque burden”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [296]
The cited source says what the claim attributes to it.
In the citing paper
“further implicating microglia in neuronal and/or synaptic loss [294–296]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [296]
In the citing paper
“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 Spangenberg et al., 2016
In the citing paper
“For instance, synaptic loss is a key feature of AD pathogenesis mediated, at least in part, by microglia [13, 79].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [13]
In the citing paper
“We previously reported that neuronal and synaptic genes (e.g. Dlk2, Kcnq3, Nrg3, Scn1b) and related functional pathways (e.g. synaptic vesicles, glutamate receptors, neuronal membranes) were extensively and uniquely downregulated in the 7mo 5xFAD hippocampus compared to WT hippocampus and other 5xFAD brain regions [12], respectively, in addition to a loss of subiculum neurons and dendritic spines”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [13]
In the citing paper
“yet the removal of the microglia at advanced stages of pathology protects against synaptic and neuronal loss10.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [10]
In the citing paper
“The absence of microglia did not significantly alter the levels of Aβ38, Aβ40, or Aβ42, in detergent-soluble or -insoluble cortical and thalamic homogenates in either the 4- or 7- month cohorts (Fig. 5a–h), in line with multiple studies showing that CSF1R inhibition does not affect Aβ production/clearance10,27,28.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [10]
In the citing paper
“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 [10]
In the citing paper
“No statistical methods were used to predetermine sample sizes; however, our sample sizes are similar to those reported in recently published similar studies10,28.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [10]
In the citing paper
“Consistent with a potential detrimental role of microglia, it was shown that ablation of microglia by a compound (PLX3397) that inhibits CSF1R did not reduce plaque burden, although it did protect synapses185.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [185]
In the citing paper
“However, global microglial depletion in AD mouse models resulted in a protective effect on synaptic health, independent of amyloid β [18, 19].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [18]
In the citing paper
“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 [38]
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Citations
Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Polazzi, E., Mengoni, I., Caprini, M., Peña‐Altamira, E., Kurtys, E., & Monti, B. (2012) · Neurosignals · doi:10.1159/000337115 · Cited by 9,023
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 · cited 4×
“The 5xfAD mice represent an aggressive model of amyloid pathologies, with amyloid-b plaques first depositing from 2 months of age (Oakley et al., 2006).”
BackgroundMethodInfluentialHarold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326
TREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
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
CSF-1R inhibition alters macrophage polarization and blocks glioma progression
Pyonteck, S. M., Akkari, L., Schuhmacher, A. J., Bowman, R. L., Sevenich, L., Quail, D. F., Olson, O. C., Quick, M. L., Huse, J. T., Teijeiro, V., et al. (2013) · Nature Medicine · doi:10.1038/nm.3337 · Cited by 2,463
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234
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
Self-citationNaj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901
Cited by
Sorted by citations
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935
“1 A; Srinivasan et al., 2016; Zhang et al., 2016).”
BackgroundDisease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474
Fricker, M., Tolkovsky, A. M., Borutaitė, V., Coleman, M. P., & Brown, G. C. (2018) · Physiological Reviews · doi:10.1152/physrev.00011.2017 · Cited by 1,148
Microglial signatures and their role in health and disease
Butovsky, O., & Weiner, H. L. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0057-5 · Cited by 1,046
Negative feedback control of neuronal activity by microglia
Badimon, A., Strasburger, H. J., Ayata, P., Chen, X., Nair, A., Ikegami, A., Hwang, P., Chan, A. T., Graves, S. M., Uweru, J. O., et al. (2020) · Nature · doi:10.1038/s41586-020-2777-8 · Cited by 979
Metadata
- Authors
- Spangenberg, E. E., Lee, R. J., Najafi, A. R., Rice, R. A., Elmore, M. R. P., Blurton-Jones, M., West, B. L., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- Plexxikon (United States) (US)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-02-26
- Volume
- 139
- Issue
- 4
- Pages
- 1265-1281
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5006229
- OpenAlex
- W2281702574
- Semantic Scholar
- 82920544f365b661b1f2e68abe91acd0c7d6f7f8
- Cited by
- 695
- References
- 88
- Citations by year
- 2026: 44 · 2025: 63 · 2024: 66 · 2023: 79 · 2022: 80 · 2021: 90 · 2020: 80 · 2019: 62 · 2018: 66 · 2017: 48 · 2016: 16
- FWCI
- 31.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Alzheimer's Association
- Glenn Foundation for Medical Research
- Plexxikon
- National Institutes of Health (UL1TR001414, AG00096, AG00538)
- National Institute on Aging (AG00096, AG 00538, P50AG016573, T32AG000096)
- National Institute of Neurological Disorders and Stroke (F31NS086409, R01NS083801)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, Alzheimer's disease, CSF1R inhibition, neuroinflammation, amyloid plaques, neuronal loss, dendritic spine loss, 5xFAD mice, contextual memory, synaptic loss
- MeSH terms
- Alzheimer Disease, Animals, Brain, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Amyloid beta-Peptides, Microglia, Mice, Mice, 129 Strain, Plaque, Amyloid
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