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.
“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]
The Results section, “Microglia do not modulate amyloid-β pathology,” reports no significant change in plaque number, size, or load after microglial depletion in 5xfAD mice. The Introduction says depletion improved memory and prevented neuronal loss, but not by decreasing plaques. The supplied passages do not give page numbers. (LLM, conf=0.94)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn mouse models of AD, genetic or pharmacological depletion of microglia prevented microglia association with amyloid plaques and neuronal loss, leading to improved learning and memory without affecting amyloid plaque load.
“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
The Introduction and the section on contextual memory report that pharmacological microglial depletion in 5xfAD mice prevented neuronal loss and reduced plaque-associated microglia; the amyloid-pathology section reports no change in plaque load. This paper does not report genetic depletion, and plaque association was reduced rather than prevented. Contextual memory improved only as a statistical trend (P = 0.0813), so the claim overstates that result. (LLM, conf=0.89)
Experimental — accuracy not yet measuredMicroglia depletion before or after Aβ pathology in AD mouse models improved contextual memory.
“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]
The contextual-memory Results section (page not provided) reports that microglia depletion in 10-month-old 5xfAD mice, which already had extensive amyloid pathology, produced a trend toward improved contextual fear-conditioning performance (P = 0.0813). The section on young 5xfAD mice reports depletion before plaque formation but measures amyloid pathology, not contextual memory. Thus the source does not support improved contextual memory from depletion before Aβ pathology, and the observed improvement after pathology was a trend rather than a statistically significant result. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSeveral groups have reported that microglial elimination via CSF1R inhibition improves behavioral performance and synaptic functioning independent of Aβ accumulation in multiple transgenic mouse models of AD (3xTg, 5xFAD, APP/PS1).
“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]
The Results on 5xfAD mice report that CSF1R inhibition eliminated microglia and increased mushroom-spine density; the Discussion reports unchanged amyloid-β levels and plaque load. But the behavioral result was only a trend toward improved contextual memory (P = 0.0813), and the paper measured spine structure rather than synaptic functioning directly. The other mouse models appear in a sentence supported by multiple citations, not as models studied in this paper. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAblation of microglia in younger mice before cerebral amyloidosis reduces Aβ deposition, while later ablation does not alter Aβ load.
“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]
Microglia are dispensable for Aβ clearance and plaque formation in late stage of disease.
“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]
Microglia ablation in AD mouse models at 10 months had no impact on plaque burden.
“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]
Microglia implicated in neuronal and/or synaptic loss.
“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]
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 Spangenberg et al., 2016
Synaptic loss is a key feature of AD pathogenesis mediated, at least in part, by microglia.
“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]
Neuronal and synaptic genes and related functional pathways were extensively and uniquely downregulated in the 7-month 5xFAD hippocampus compared to WT hippocampus and other 5xFAD brain regions, and subiculum neurons and dendritic spines were lost in 10-month-old 5xFAD mice.
“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]
Removal of microglia at advanced stages of pathology protects against synaptic and neuronal loss.
“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]
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.
“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]
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 [10]
No statistical methods were used to predetermine sample sizes; however, the sample sizes are similar to those reported in recently published similar studies.
“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]
Ablation of microglia by PLX3397, a CSF1R inhibitor, did not reduce plaque burden but did protect synapses.
“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]
Global microglial depletion in Alzheimer's disease mouse models resulted in a protective effect on synaptic health, independent of amyloid β.
“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]
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 [38]
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- 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
- Health Sciences › Medicine › Physiology › 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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