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Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology
Open accessAbstract
Microglial cells closely interact with senile plaques in Alzheimer's disease and acquire the morphological appearance of an activated phenotype. The significance of this microglial phenotype and the impact of microglia for disease progression have remained controversial. To uncover and characterize putative changes in the functionality of microglia during Alzheimer's disease, we directly assessed microglial behavior in two mouse models of Alzheimer's disease. Using in vivo two-photon microscopy and acute brain slice preparations, we found that important microglial functions - directed process motility and phagocytic activity - were strongly impaired in mice with Alzheimer's disease-like pathology compared to age-matched non-transgenic animals. Notably, impairment of microglial function temporally and spatially correlated with Aβ plaque deposition, and phagocytic capacity of microglia could be restored by interventionally decreasing amyloid burden by Aβ vaccination. These data suggest that major microglial functions progressively decline in Alzheimer's disease with the appearance of Aβ plaques, and that this functional impairment is reversible by lowering Aβ burden, e.g. by means of Aβ vaccination.
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“Notably, previous studies have shown that microglial function may be adversely affected by Aβ, particularly as a result of chronic exposure to pro-inflammatory cytokines, resulting in increased Aβ accumulation and potentially underpinning the contradiction between our in vitro and in vivo results.39,40”
From Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [39]
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“the ability of microglia to remove Αβ declines over time”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [17]
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“supporting that the progression of amyloid pathology correlates with impaired capacity of microglia to phagocytose Αβ17,16.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [17]
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“their phagocytic capacity declines with aging, chronic exposure to Αβ, and during sustained inflammation in the AD brain76,16,17.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [17]
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“However, perturbations in microglial activity, often associated with aging, can affect the effective clearance of these neuron-derived Aβ fibrils, leading to increased plaque formation and the progression of cognitive and behavioral impairments (17–20).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [19]
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“Microglial phagocytosis is believed to be dysfunctional in AD [17–19].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [18]
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“However, several studies have shown that defects in the phagocytic function of microglia can be restored with Aβ immunization [18, 23] and anti-inflammatory drug treatment [24, 25].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [18]
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“Notably, microglial process motility directed toward site of damage was significantly impaired in mice with A β plaques 48 .”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [48]
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Citations
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PANoptosis: Potential Therapeutic Prospects in Alzheimer's Disease
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“Notably, widespread Aβ plaque deposition across multiple brain regions overwhelms microglial clearance capacity, establishing self-perpetuating pathological cycles (Hickman et al. 2008; Thériault et al. 2015; Frackowiak et al. 1992; Krabbe et al. 2013).”
Electrophysiological insights into Alzheimer's disease: A review of human and animal studies
Calvin, K., McNeela, A. M., Osse, A. M. L., Bhasin, G., Ridenour, M., Kinney, J. W., & Hyman, J. M. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105987 · Cited by 8
Effects of Curcumin on Neuroinflammation in Animal Models and in Patients with Alzheimer Disease
Farooqui, A. A. (2016) · Springer eBooks · doi:10.1007/978-3-319-15889-1_7 · Cited by 6
Fibroblast-Conditioned Media Enhance the Yield of Microglia Isolated from Mixed Glial Cultures
HU, J. L., Wang, P., Wang, Z., Xu, Y., Peng, W., Chen, X., Fang, Y., Zhu, L., Wang, D., Wang, X., et al. (2022) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-022-01193-9 · Cited by 6
Izquierdo, P., Jolivet, R., Attwell, D., & Madry, C. (2023) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-023-02871-3 · Cited by 7
“We first assessed whether microglial morphology was affected by proximity to Aβ plaques, as has been shown previously in other non-knock-in models of AD, which have a differing development of disease parameters [4, 35, 54].”
BackgroundDistribution of translation initiation factor eIF3 in neutrophils in Alzheimer disease
Ivanov, P. A., Mikhaylova, N. M., & Klyushnik, T. P. (2016) · Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology · doi:10.1134/s1990747816030053 · Cited by 5
“It was shown also that the phagocytic activity of these cells is considerably reduced in AD and the β-amyloid clearance is therefore decelerated [3].”
The Amyloid-beta rich CNS environment alters myeloid cell functionality independent of their origin
Drost, N., Houtman, J., Cseresnyés, Z., Niesner, R. A., Rinnenthal, J.-L., Miller, K. R., Prokop, S., & Heppner, F. L. (2020) · Scientific Reports · doi:10.1038/s41598-020-63989-3 · Cited by 5
Self-citationCan MRI T1 be used to detect early changes in 5xFAD Alzheimer’s mouse brain?
Spencer, N. G., Lovell, D. P., Elderfield, K., Austen, B., & Howe, F. A. (2016) · Magnetic Resonance Materials in Physics Biology and Medicine · doi:10.1007/s10334-016-0593-9 · Cited by 5
Bergendorf, A. M., Park, J. H., Ball, B. K., & Brubaker, D. K. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.07.637100 · Cited by 5
“Microglia have been shown to be inefficient at performing phagocytosis dependent on amyloid plaque levels in mice (9).”
CD38-NAD(+) Axis: New Insights into Glaucoma Therapy
Zhang, W., Zheng, H., Pang, Y., Wang, Y., & Zhang, X. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05243-3 · Cited by 6
Moreno, O., Fernández, I., Plaza‐García, S., Padró, D., Baz, Z., Ramos‐Cabrer, P., Martín, A., & Llop, J. (2026) · NeuroImage · doi:10.1016/j.neuroimage.2026.121753 · Cited by 5
Adnan, M., Siddiqui, A. J., Bardakçi, F., Surti, M., Badraoui, R., & Patel, M. B. (2025) · Pharmaceuticals · doi:10.3390/ph18060921 · Cited by 4
“These plaques are associated with neuroinflammatory responses, where activated microglia and astrocytes release pro-inflammatory cytokines and reactive oxygen species, further intensifying neuronal damage [8,12].”
Minochkin, A. K., Lobzin, V. Y., Николаевна, С. Н., Попов, О. С., Апалько, С. В., & Sherbak, S. G. (2022) · Neurology neuropsychiatry Psychosomatics · doi:10.14412/2074-2711-2022-2-35-42 · Cited by 5
Comparative Anatomy of Glial Cells in Mammals
Reichenbach, A., & Bringmann, A. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-820584-6.00016-7 · Cited by 4
Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic
Logiacco, F., Grzegorzek, L. C., Cordell, E., Popp, O., Mertins, P., Gutmann, D. H., Kettenmann, H., & Semtner, M. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01525-w · Cited by 4
“In the early stages of Alzheimer’s disease, microglia facilitate the destruction of neuronal networks due to their ability to prune synapses [29, 29, 30, 30, 34], whereas the loss of phagocytic and surveillance activity contributes to enhanced Aß plaque burden at later stages [35, 67].”
BackgroundSelf-citationNeuroinflammation in Alzheimer's disease
Agrawal, M., Singhal, M., Prajapati, B. G., Chaudhary, H., Jasoria, Y., Kumar, B., Arora, M. K., & Sahoo, J. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-13205-6.00003-0 · Cited by 4
Crockett, A. M., Fuhrmann, M., Garaschuk, O., & Davalos, D. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_5 · Cited by 4
Reestablishing microglia function: good news for Alzheimer's therapy?
Biber, K. (2017) · The EMBO Journal · doi:10.15252/embj.201796627 · Cited by 3
“Impaired uptake of A b peptides and microglia dysfunction was described in mouse models of AD (Hickman et al , 2008; Krabbe et al , 2013; Orre et al , 2014; Hellwig et al , 2015).”
Targeting Alzheimer's disease hallmarks with the Nrf2 activator IsoeugenolPreprint
da Silva, A. B. G., Silva, S., Macêdo, J. N. A., Moreira, P., Baptista, D., Bicker, J., Fortuna, A. C., Liberal, J. M. T., Rodrigues, B. R. I., Resende, R., et al. (2023) · Qeios · doi:10.32388/luxm7w · Cited by 4
Xie, D., Zheng, Q., Lv, J., Zhang, Q., Cui, Z., Huang, S., Yu, W., Chen, B., Que, W., Fu, S., et al. (2025) · Advanced Science · doi:10.1002/advs.202510270 · Cited by 3
Quipildor, G. F., Belfiore, R., Althobaiti, K., Najarzadeh, Z., Glabe, C. C., Readhead, B. P., Gandy, S., Salton, S. R., & Ehrlich, M. E. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-025-00012-x · Cited by 6
“In AD mouse models, early microglial activation, during the formation of Aβ plaques, appears to be beneficial, while after prolonged activation, microglial phagocytosis and clearance of plaques is reduced [63, 64].”
Toubasi, A. A., & Al‐Sayegh, T. N. (2026) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.70270 · Cited by 3
Chen, H., Cao, J., Zhang, Y., Su, X., Kang, Y., Gao, L., & Jing, Y. (2025) · The FASEB Journal · doi:10.1096/fj.202501545rr · Cited by 4
“However, with increased age, Aβ plaques lead to microglial dysfunction, resulting in a decline in Aβ phagocytosis and clearance, and an increase in inflammation [60].”
Lipid-nanoparticle-induced vacuolization in microglia
Kerschbaum, H., Gerner, C., Oberascher, K., Steiner, P., Schürz, M., & Bresgen, N. (2024) · Communications Biology · doi:10.1038/s42003-024-07271-6 · Cited by 2
“In transgenic AD mice, microglia phagocyte amyloid-containingneuritesinpre-plaqueanimals 49 ,phagocyteA β plaques in a later stage 50 , but declines in phagocytic activity as A β deposition increases 51,52 .”
Molecular Targeting and Translational Research for New Therapeutic Strategies on Alzheimer's Disease
Takata, K. (2013) · YAKUGAKU ZASSHI · doi:10.1248/yakushi.13-00219 · Cited by 3
Functional properties of microglia in mouse models of Alzheimer’s disease
Saiepour, N. (2017) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-6117 · Cited by 3
Microglial amyloid beta clearance is driven by PIEZO1 channelsPreprint
Konttinen, H., Sitnikova, V., Ishchenko, Y., Shakirzyanova, A., Giudice, L., Ugidos, I. F., Gómez‐Budia, M., Korvenlaita, N., Ohtonen, S., Belaya, I., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.18.484831 · Cited by 3
Jury-Garfe, N., You, Y.-W., Martínez, P., Redding-Ochoa, J., Karahan, H., Johnson, T., Zhang, J., Kim, J., Troncoso, J., & Lasagna-Reeves, C. A. (2023) · bioRxiv · doi:10.1101/2023.07.27.550884 · Cited by 2
LeVasseur, H. L., & Zhou, B. (2025) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2025.578711 · Cited by 2
Sennoside A alleviating cognitive impairment in APP/PS1 mice via balancing microbiome metabolism
Shi, Y., Ma, H., Li, H., Wang, Y., Wang, C., Zhang, N., Luo, G., Wang, Y., & Gao, X. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251389922 · Cited by 2
“31,32 As expected, we observed that SA signi fi cantly reduced A β deposition and tau aggregation in APP/PS1 mice.”
Cangalaya, C., Düsedau, H. P., Dunay, I. R., Dityatev, A. E., & Stoyanov, S. (2026) · Cells · doi:10.3390/cells15020182 · Cited by 3
“This is in line with previous studies showing that microglial phagocytic activity and cortical A β plaque burden exhibited a significant inverse correlation in APPPS1 mice [34].”
N-3 PUFAs and neuroinflammatory processes in cognitive disorders
Leyrolle, Q., Layé, S., & Nadjar, A. (2016) · OCL · doi:10.1051/ocl/2015064 · Cited by 4
“Neuroinflammation is recognised for its overall role in Alzheimer Disease (AD) pathology, including the acceleration of neuronal loss and amyloid beta (Aβ) and Tau mysfolding and deposition (Krabbe et al., 2013; Krstic et al., 2012).”
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“Alterna-tively, it was shown that microglial phagocytic capacity for Aβ was impaired in the mice with AD disease pathology as compared to age-matched controls which was partially restored by decreasing the amyloid burden by Aβ vaccination [82].”
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Neuroinflammation in Alzheimer's Disease
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Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves CognitionPreprint
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“In accordance, microglial motility in the presence of Aβ plaques was found to be decreased in APPPS1 mice compared to control mice when a focal lesion was performed by a laser [56].”
BackgroundSelf-citation
Metadata
- Authors
- Krabbe, G., Halle, A., Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., Miller, K. R., Prokop, S., Kettenmann, H., & Heppner, F. L.
- Affiliations
- Max Delbrück Center (DE)
- Center of Advanced European Studies and Research (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Kettenmann, Helmut
- Heppner, Frank L.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-04-08
- Volume
- 8
- Issue
- 4
- Pages
- e60921
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3620049
- OpenAlex
- W2044090829
- Cited by
- 478
- References
- 41
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 31 · 2023: 25 · 2022: 44 · 2021: 56 · 2020: 40 · 2019: 41 · 2018: 38 · 2017: 38 · 2016: 33 · 2015: 39 · 2014: 34 · 2013: 13
- FWCI
- 22.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Max Planck Digital Library (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- European Commission (FP7 HEALTH)
- Deutsche Forschungsgemeinschaft (SFB TRR 43, NeuroCure EXC257, GRK1258, EXC257)
- Jung-Stiftung für Wissenschaft und Forschung
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS046006, NS046006)
- FP7 Health
- 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, amyloid plaques, microglial activation, microglial phagocytosis, mouse models of Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Cell Movement, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Mutation, Phagocytosis, Amyloid beta-Peptides, Protein Structure, Secondary, Microglia, Mice, Protein Multimerization, Plaque, Amyloid, Spatio-Temporal Analysis
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