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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Microglial function may be adversely affected by Aβ, particularly as a result of chronic exposure to pro-inflammatory cytokines, resulting in increased Aβ accumulation.
“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 <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [39]
The Discussion (page unavailable) proposes that chronic exposure to a pro-inflammatory environment may impair microglial function and reports that TNFα reduces Aβ phagocytosis in vitro. It also links impaired phagocytosis with plaque burden, but does not establish that cytokine-driven impairment results in increased Aβ accumulation. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe ability of microglia to remove Aβ declines over time.
“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]
The Results section (page unavailable) shows that microglial phagocytic activity becomes impaired as Aβ plaques appear in APPPS1 mice. However, the study measured general phagocytic activity, not a decline in Aβ removal itself; the Discussion says the finding may explain why microglia fail to remove plaques sufficiently. (LLM, conf=0.86)
Experimental — accuracy not yet measuredProgression of amyloid pathology correlates with impaired capacity of microglia to phagocytose Aβ.
“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]
The Results section reports a significant inverse correlation between Aβ plaque burden and microglial phagocytic activity in APPPS1 mice (ρ = −0.75, p = 0.0014). But the Methods section says phagocytosis was measured by uptake of fluorescent microspheres, not Aβ itself, so the source does not directly establish impaired capacity to phagocytose Aβ. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMicroglial phagocytic capacity declines with aging, chronic exposure to Aβ, and during sustained inflammation in the AD brain.
“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]
The Results section reports reduced microglial phagocytosis where Aβ plaques were present in Alzheimer-like mice, but normal capacity in plaque-free regions, including as the mice aged. The Discussion proposes sustained inflammation as a possible explanation rather than establishing it as a cause. The paper therefore supports plaque-associated decline, not the full claim that aging, chronic Aβ exposure, and sustained inflammation each cause decline in the AD brain. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPerturbations in microglial activity, often associated with aging, can affect the effective clearance of neuron-derived Aβ fibrils, leading to increased plaque formation and progression of cognitive and behavioral impairments.
“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]
The Introduction says microglia can take up fibrillar Aβ, and the Results show that impaired phagocytosis coincides with plaque deposition in Alzheimer-like mice. But the paper does not establish that impaired clearance causes increased plaque formation or cognitive and behavioral decline. Its Discussion also argues against aging-related microglial senescence as the main cause of the dysfunction observed here. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Microglial phagocytosis is believed to be dysfunctional in AD.
“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]
Defects in the phagocytic function of microglia can be restored with Aβ immunization and anti-inflammatory drug treatment.
“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]
Microglial process motility directed toward site of damage was significantly impaired in mice with Aβ plaques.
“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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Cites
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ResultThe microglial "activation" continuum: from innate to adaptive responses
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Self-citationMicroglia Mediate the Clearance of Soluble Aβ through Fluid Phase Macropinocytosis
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“Further studies found that microglial cells internalize soluble, protofibrillar and fibrillar forms of Ab [9,17,18] in vitro and in vivo by several mechanisms such as macropinocytosis or endocytosis, highlighting the general aptitude of microglia to remove Ab.”
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“The Ab plaque-associated functional decline of microglia we have shown here may explain why temporary ablation of microglia for up to 30 days in APPPS1 mice does not change the formation and maintenance of Ab burden [19].”
BackgroundSelf-citationMicroglial Activation Resulting from CD40-CD40L Interaction After β-Amyloid Stimulation
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MethodSelf-citationKoenigsknecht-Talboo, J., Meyer-Luehmann, M., Parsadanian, M., Garcia-Alloza, M., Finn, M. B., Hyman, B. T., Bacskai, B. J., & Holtzman, D. M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4147-08.2008 · Cited by 149 · cited 3× · see citing works
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“Primary Microglial Cell Culture Microglial cultures were prepared from cerebral cortex of 1–3 day old APPPS1 and wildtype mice as previously described [24] and cultured in DMEM supplemented with 10% fetal calf serum, 2 mM L-glutamine, 100 units/ml penicillin and 100 mg/ml streptomycin.”
MethodSelf-citationγ‐Secretase component presenilin is important for microglia β‐amyloid clearance
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“…activation of microglia is accompanied by diminished phagocytosis and the more abundant secretion of pro-in fl ammatory cytokines, leading to the accumulation of A β and the ampli fi cation of neuroin fl ammation (El Khoury et al., 2007; Hickman et al., 2008; Krabbe et al., 2013; Heneka et al., 2015).”
Transcriptomic analysis of purified human cortical microglia reveals age-associated changes
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“Notably, microglial process motility directed toward site of damage was significantly impaired in mice with A β plaques 48 .”
BackgroundResultMicroglial dysfunction in brain aging and Alzheimer's disease
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“A recent study showed that microglial phagocytic capacity is impaired in late stages of cerebral amyloidosis [142], and in vitro studies using microglia cultured from adult animals have shown that aged microglia internalize less Ab peptide than young cells [113,143].”
BackgroundNew insights on the role of microglia in synaptic pruning in health and disease
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“, in models of Alzheimer’s disease with amyloid b plaque deposition (Koenigsknecht-Talboo et al., 2008; Krabbe et al., 2013; Condello et al., 2015) raises the question of whether the dependence of surveillance on THIK-1 activity can be employed therapeutically.”
BackgroundMicroglia and Astrocytes in Alzheimer's Disease: Implications for Therapy
Fakhoury, M. (2017) · Current Neuropharmacology · doi:10.2174/1570159x15666170720095240 · Cited by 482 · see citing works
“Consistent with the view that microglia are involved in Aβ clearance, impairment of microglia function in transgenic mice facilitates the progression of AD and results in increased Aβ accumulation in the brain [61, 62].”
BackgroundMarsh, S. E., Abud, E. M., Lakatos, A., Karimzadeh, A., Yeung, S. T., Davtyan, H., Fote, G. M., Lau, L., Weinger, J. G., Lane, T. E., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525466113 · Cited by 411 · see citing works
“However, chronic activation of these cells shift microglia to a more proinflammatory and less phagocytic state (9, 10).”
BackgroundIl10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology
Guillot-Sestier, M.-V., Doty, K. R., Gate, D., Rodriguez, J., Leung, B. P., Rezai-Zadeh, K., & Town, T. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.068 · Cited by 363 · see citing works
“Microglial ‘‘paralysis’’ may be owed to increasing Ab burden with disease progression, as shown by others in vitro and in vivo (Korotzer et al., 1993; Krabbe et al., 2013; Michelucci et al., 2009).”
Butovsky, O., Jedrychowski, M. P., Cialic, R., Krasemann, S., Murugaiyan, G., Fanek, Z., Greco, D. J., Wu, P. M., Doykan, C. E., Kiner, O., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24304 · Cited by 358 · see citing works
Microglia: Agents of the CNS Pro-Inflammatory Response
Rodríguez-Gómez, J. A., Kavanagh, E., Engskog-Vlachos, P., Engskog, M. K. R., Herrera, A. J., Espinosa-Oliva, A. M., Joseph, B., Hajji, N., Venero, J. L., & Burguillos, M. A. (2020) · Cells · doi:10.3390/cells9071717 · Cited by 365 · see citing works
Microglia-Mediated Synapse Loss in Alzheimer's Disease
Rajendran, L., & Paolicelli, R. C. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.1136-17.2017 · Cited by 355 · see citing works
“However, in vivo two-photon imaging studies have revealed that A deposition coincides with functional impairment of microglia, suggesting that, in advanced pathological stages, microglia become unable to remove and clear the amyloid burden (Krabbe et al., 2013).”
BackgroundThe Microbiota–Gut–Brain Axis and Alzheimer’s Disease: Neuroinflammation Is to Blame?
Megur, A., Baltriukienė, D., Bukelskienė, V., & Burokas, A. (2020) · Nutrients · doi:10.3390/nu13010037 · Cited by 323 · see citing works
“On the other hand, the activated microglia lose their phagocytic effect, thus decreasing the degree of Aβ phagocytosis, inevitably developing its accumulation [162].”
BackgroundStreit, W. J., Xue, Q.-S., Tischer, J., & Bechmann, I. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0142-6 · Cited by 317 · see citing works
“Multiple lines of evidence have suggested that amyloid plaques accumulate and persist because dysfunctional microglia are unable to remove them [3,56,161-163].”
BackgroundChronic stress and glucocorticoids: From neuronal plasticity to neurodegeneration
Vyas, S., Rodrigues, A. J., Silva, J. M., Tronche, F., Almeida, O. F. X., Sousa, N., & Sotiropoulos, I. (2016) · Neural Plasticity · doi:10.1155/2016/6391686 · Cited by 297 · see citing works
RETRACTED: Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases
Rauf, A., Badoni, H., Abu-Izneid, T., Olatunde, A., Rahman, M., Painuli, S., Semwal, P., Wilairatana, P., & Mubarak, M. (2022) · Molecules · doi:10.3390/molecules27103194 · Cited by 273 · see citing works
“At the same time, it was observed that the capacity of microglia to form pro-inflammatory cytokines is not altered [68,69].”
BackgroundRetractedNeuroinflammation in Alzheimer’s Disease
Onyango, I. G., Jauregui, G. V., Čarná, M., Bennett, J. P., & Stokin, G. B. (2021) · Biomedicines · doi:10.3390/biomedicines9050524 · Cited by 330 · see citing works
“In AD, the accumulation of Aβ throughout the brain results partly from the failure of microglia to remove extracellular Aβ [126–128] and AD cortical specimens reveal that the microglia surrounding plaques have impaired Aβ uptake [127,129,130].”
BackgroundMicroglial phenotypes in Parkinson’s disease and animal models of the disease
Joers, V., Tansey, M. G., Mulas, G., & Carta, A. R. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.04.006 · Cited by 285 · see citing works
“Furthermore, in a mouse model of Alzheimer’s disease, the phagocytic capacity of microglia was reduced and inversely correlated to the Aβ plaque burden, suggesting that microglia function declined with severity of disease (Krabbe et al., 2013).”
BackgroundMicroglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau
Kang, S. S., Ebbert, M. T. W., Baker, K. E., Cook, C., Wang, X., Sens, J. P., Kocher, J.-P., Petrucelli, L., & Fryer, J. D. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180653 · Cited by 260 · see citing works
“3, E and F), suggesting that Cst7 induction in microglial cells may contribute to the decreased phagocytic activity observed during amyloidosis, tauopathy, or aging (Krabbe et al., 2013; Keren-Shaul et al., 2017; Koellhoffer et al., 2017; Salter and Stevens, 2017).”
BackgroundAging and Alzheimer's disease: comparison and associations from molecular to system level
Xia, X., Jiang, Q., McDermott, J., & Han, J. J. (2018) · Aging Cell · doi:10.1111/acel.12802 · Cited by 301 · see citing works
Microglia actions in Alzheimer's disease
Prokop, S., Miller, K. R., & Heppner, F. L. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1182-x · Cited by 291 · see citing works
Self-citationLonnemann, N., Hosseini, S., Marchetti, C., Skouras, D. B., Stefanoni, D., D’Alessandro, A., Dinarello, C. A., & Korte, M. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2009680117 · Cited by 298 · see citing works
“On the other hand, microglia cells react very sensitively to inflammatory processes by changing their morphological shape and have been consequently described as having an “ activated ” phenotype (36, 65, 66).”
The good, the bad, and the opportunities of the complement system in neurodegenerative disease
Schartz, N. D., & Tenner, A. J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-02024-8 · Cited by 283 · see citing works
“come dysfunctional, and thus, the phagocytosis and clearance of Aß is reduced [169] while inflammation increases.”
BackgroundMicroglia and the aging brain: are senescent microglia the key to neurodegeneration?
Angelova, D. M., & Brown, D. R. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14860 · Cited by 262 · see citing works
“It is possible that iron accumulation in microglia could be a protective mechanism from iron toxicity in the brain which then can proceed to damage the microglia themselves and induce the accelerated aging signature seen in neurodegeneration (Krabbe et al. 2013).”
BackgroundClearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes
Zuroff, L. R., Daley, D. A., Black, K. L., & Koronyo‐Hamaoui, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2463-7 · Cited by 275 · see citing works
Blood-brain barrier permeability and physical exercise
Małkiewicz, M. A., Szarmach, A., Sabisz, A., Cubała, W. J., Szurowska, E., & Winklewski, P. J. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1403-x · Cited by 276 · see citing works
The Impact of Disease Comorbidities in Alzheimer’s Disease
Santiago, J. A., & Potashkin, J. A. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.631770 · Cited by 259 · see citing works
Beyond Activation: Characterizing Microglial Functional Phenotypes
Lier, J., Streit, W. J., & Bechmann, I. (2021) · Cells · doi:10.3390/cells10092236 · Cited by 274 · see citing works
Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities
Hemonnot, A.-L., Hua, J., Ulmann, L., & Hirbec, H. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00233 · Cited by 298 · see citing works
Unger, M. S., Li, E., Scharnagl, L., Poupardin, R., Altendorfer, B., Mrowetz, H., Hutter-Paier, B., Weiger, T. M., Heneka, M. T., Attems, J., et al. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.05.070 · Cited by 248 · see citing works
Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease
Rajesh, Y., & Kanneganti, T. (2022) · Cells · doi:10.3390/cells11121885 · Cited by 261 · see citing works
Lee, J.-W., Nam, H., Kim, L. E., Jeon, Y., Min, H., Ha, S., Lee, Y., Kim, S.-Y., Lee, S. J., Kim, E.-K., et al. (2019) · Autophagy · doi:10.1080/15548627.2018.1556946 · Cited by 260 · see citing works
“Notably, in the brains of patients with neurodegenerative diseases such as AD, the ability of microglia to phagocytose and degrade Aβ is reduced [54,67,68].”
BackgroundNeuroinflammation in Alzheimer&rsquo;s disease
Zhang, F., & Jiang, L. (2015) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s75546 · Cited by 276 · see citing works
“Major microglial functions progressively decline with the appearance of Aβ plaques in AD, and lowering Aβ burden could reverse this functional impairment.(36) Microglia interact with Aβ, overproduction of inflammatory cytokines (IL-1β, TNF-α, IL-6) and substances released by dying neurons, activated β-secretase-1 (BAC…”
BackgroundHussain, B., Fang, C., & Chang, J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.688090 · Cited by 251 · see citing works
Davies, D. S., Ma, J., Jegathees, T., & Goldsbury, C. (2017) · Brain Pathology · doi:10.1111/bpa.12456 · Cited by 251 · see citing works
Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease
Yin, Z., Raj, D., Saiepour, N., Van Dam, D., Brouwer, N., Holtman, I. R., Eggen, B. J. L., Möller, T., Tamm, J. A., Abdourahman, A., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.03.021 · Cited by 238 · see citing works
“On the other hand, microglia show a pronounced reduction in motility (Krabbe et al., 2013) and reduced phagocytic capacity in brain slice cultures (Hellwig et al., 2015).”
Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models
Minami, S. S., Min, S.-W., Krabbe, G., Wang, C., Zhou, Y., Asgarov, R., Li, Y., Martens, L. H., Elia, L. P., Ward, M. E., et al. (2014) · Nature Medicine · doi:10.1038/nm.3672 · Cited by 237 · see citing works
Self-citationMorris, G. P., Clark, I. A., Zinn, R., & Vissel, B. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.07.002 · Cited by 236 · see citing works
“, 2004), and this correlates with amyloid-b deposition (Krabbe et al., 2013).”
BackgroundBaik, S. H., Kang, S., Son, S. M., & Mook-Jung, I. (2016) · Glia · doi:10.1002/glia.23074 · Cited by 234 · see citing works
“Furthermore, several studies have shown that microglia are impaired func- tionally and physiologically in AD (Brawek et al., 2014; Krabbe et al., 2013; Zhang et al., 2014).”
BackgroundTargeting Neuroinflammation to Treat Alzheimer’s Disease
Ardura-Fabregat, A., Boddeke, E., Boza‐Serrano, A., Brioschi, S., Castro‐Gomez, S., Ceyzériat, K., Dansokho, C., Dierkes, T., Gelders, G., Heneka, M. T., et al. (2017) · CNS Drugs · doi:10.1007/s40263-017-0483-3 · Cited by 236 · see citing works
“specimens from patients with AD, the microglia surrounding plaques are impaired at Ab uptake [15, 17, 18].”
BackgroundThe dynamics of monocytes and microglia in Alzheimer’s disease
Thériault, P., ElAli, A., & Rivest, S. (2015) · Alzheimer s Research & Therapy · doi:10.1186/s13195-015-0125-2 · Cited by 230 · see citing works
Mattei, D., Ivanov, A., Ferrai, C., Jordan, P., Guneykaya, D., Buonfiglioli, A., Schaafsma, W., Przanowski, P., Deuther-Conrad, W., Brust, P., et al. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.80 · Cited by 222 · see citing works
Self-citationBenarroch, E. E. (2013) · Neurology · doi:10.1212/wnl.0b013e3182a4a577 · Cited by 222 · see citing works
“Studies using acute brain slice preparations from mice with AD-like pathology show that impaired motility and phagocytic activity of microglia correlated with Ab plaque burden and could be restored by decreasing this burden by Ab vaccination.(81) These findings provide a rationale for promoting perivascular macrophage…”
Microglia contribute to the propagation of Aβ into unaffected brain tissue
d’Errico, P., Ziegler-Waldkirch, S., Aires, V., Hoffmann, P., Mezö, C., Erny, D., Monasor, L. S., Liebscher, S., Ravi, V. M., Joseph, K., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-00951-0 · Cited by 214 · see citing works
Beclin1‐driven autophagy modulates the inflammatory response of microglia via NLRP3
Houtman, J., Freitag, K., Gimber, N., Schmoranzer, J., Heppner, F. L., & Jendrach, M. (2019) · The EMBO Journal · doi:10.15252/embj.201899430 · Cited by 212 · see citing works
“The sum of the products in each group was then termed and displayed as phagocytic index (Krabbe et al , 2013).”
Self-citationThe role of the immune system in Alzheimer disease: Etiology and treatment
Jevtic, S. D., Sengar, A. S., Salter, M. W., & McLaurin, J. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.005 · Cited by 218 · see citing works
Microglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan
Tay, T. L., Béchade, C., D’Andrea, I., St‐Pierre, M., Henry, M. S., Roumier, A., & Tremblay, M. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00421 · Cited by 211 · see citing works
“Using acute hippocampal slices from 7 to 9-week old APP/PS1 mice, the phagocytic ability of microglia was also shown to be compromised in amyloid β plaque-burdened areas specifically (Krabbe et al., 2013).”
BackgroundOxidized cholesterol as the driving force behind the development of Alzheimer’s disease
Gamba, P., Testa, G., Gargiulo, S., Staurenghi, E., Poli, G., & Leonarduzzi, G. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00119 · Cited by 202 · see citing works
“Potentially these oxysterols, as well as other cholesterol metabolites, can cross the BBB.”
BackgroundChen, T., Dai, Y., Hu, C., Lin, Z., Wang, S., Yang, J., Zeng, L., Li, S., & Li, W. (2024) · Fluids and Barriers of the CNS · doi:10.1186/s12987-024-00557-1 · Cited by 201 · see citing works
“However, prolonged inflammation impairs the microglial cells’ ability to bind and phagocytose Aβ, diminishes the activity of Aβ-degrading enzymes, and weakens their capacity to disintegrate Aβ plaques [199, 200].”
BackgroundSong, C., Shieh, C., Wu, Y.-S., Kalueff, A. V., Gaikwad, S., & Su, K. (2016) · Progress in Lipid Research · doi:10.1016/j.plipres.2015.12.003 · Cited by 191 · see citing works
New role of P2X7 receptor in an Alzheimer’s disease mouse model
Martin, E., Amar, M., Dalle, C., Youssef, I., Boucher, C., Le Duigou, C., Brückner, M., Prigent, A., Sazdovitch, V., Halle, A., et al. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0108-3 · Cited by 187 · see citing works
“Microglial phagocytic activity was quantified in acute brain slices from 16-month-old male mice, as previously described [33].”
BackgroundMethodSelf-citationFerretti, M. T., Merlini, M., Späni, C. B., Gericke, C., Schweizer, N., Enzmann, G. U., Engelhardt, B., Kulic, L., Suter, T. B., & Nitsch, R. M. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.02.009 · Cited by 174 · see citing works
Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction
Konishi, H., Okamoto, T., Hara, Y., Komine, O., Tamada, H., Maeda, M., Osako, F., Kobayashi, M., Nishiyama, A., Kataoka, Y., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020104464 · Cited by 179 · see citing works
“In addition to epileptic injury, dysfunction of microglial phagocytosis is suggested to be associated with neurodegenerative diseases such as Alzheimer’s disease (Krabbe et al, 2013; Lucin et al, 2013; Gabande-Rodriguez et al, 2020).”
BackgroundYoung microglia restore amyloid plaque clearance of aged microglia
Daria, A., Colombo, A., Llovera, G., Hampel, H., Willem, M., Liesz, A., Haass, C., & Tahirovic, S. (2017) · The EMBO Journal · doi:10.15252/embj.201694591 · Cited by 174 · see citing works
“Several studies proposed that microglia/macrophages are involved in the clearance of A b (Rogers et al , 2002; Simard et al , 2006; El Khoury et al , 2007; Bolmont et al , 2008; Lee & Landreth, 2010; Liu et al , 2010; Krabbe et al , 2013).”
Savage, J. C., Jay, T., Goduni, E., Quigley, C., Mariani, M. M., Malm, T., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.4586-14.2015 · Cited by 154 · see citing works
“9A,B), as previously reported in APPPS1 and APP23 mice (Krabbe et al., 2013).”
BackgroundMethodInfluentialHypothalamic innate immune reaction in obesity
Kälin, S., Heppner, F. L., Bechmann, I., Prinz, M., Tschöp, M. H., & Yi, C.-X. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.48 · Cited by 167 · see citing works
Self-citationGuedes, J. R., Custódia, C. M., Silva, R. J., de Almeida, L. P., Pedroso de Lima, M. C., & Cardoso, A. L. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu348 · Cited by 150 · see citing works
Microglia plasticity during health and disease: An immunological perspective
Shemer, A., Erny, D., Jung, S., & Prinz, M. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.08.003 · Cited by 168 · see citing works
Martin, E., Boucher, C., Fontaine, B., & Delarasse, C. (2017) · Aging Cell · doi:10.1111/acel.12522 · Cited by 156 · see citing works
“Experimental models using bone marrow chimeric mice or microglial ablation systems have shown that microglia appear to have a deficient role in AD with motility and phagocytic activities impaired (Grathwohl et al., 2009; Krabbe et al., 2013), while MDM seem to contribute more efficiently to the elimination of Ab plaqu…”
BackgroundInfluentialThe NLRP3 inflammasome triggers sterile neuroinflammation and Alzheimer’s disease
Milner, M. T., Maddugoda, M. P., Götz, J., Burgener, S. S., & Schroder, K. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.10.011 · Cited by 159 · see citing works
Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models
Johansson, J. U., Woodling, N. S., Wang, Q., Panchal, M., Liang, X., Trueba-Saiz, A., Brown, H. D., Mhatre, S. D., Loui, T., & Andreasson, K. I. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77487 · Cited by 161 · see citing works
“Moreover, prolonged exposure to proinflammatory cytokines or accumulating A β 42 peptides cause microglia to lose their normal abilities to clear toxic proteins and control inflammation (13, 14), a detrimental phenotype in the context of age-associated A β 42 accumulation.”
Microglia change from a reactive to an age-like phenotype with the time in culture
Caldeira, C., Oliveira, A. F., Cunha, C., Vaz, A. R., Falcão, A. S., Fernandes, A., & Brites, D. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00152 · Cited by 156 · see citing works
“In addition, these cells were analyzed either 24–48 h after isolation (Njie et al., 2012; Lai et al., 2013) or following trypsinization when kept in culture for several weeks in the presence of conditioned medium containing increased levels of mitogens (von Bernhardi et al., 2011).”
BackgroundMethodResultInfluentialNeuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?
Stuckey, S. M., Ong, L. K., Collins‐Praino, L. E., & Turner, R. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313101 · Cited by 157 · see citing works
“Specifically, an Alzheimer’s study in APPPS1 mice (a transgenic mouse model of cerebral amyloidosis) found that microglial directed process extension and phagocytic activity were strongly impaired in mice with Alzheimer’s diseaselike pathology [213].”
BackgroundGenetics of Alzheimer's Disease
Guerreiro, R. J., & Hardy, J. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0295-9 · Cited by 158 · see citing works
“In AD, microglial cells are attracted to βamyloid plaques, produce elevated levels of proinflammatory cytokines and reactive oxygen species, and exhibit a change in morphology [38].”
BackgroundBoyd, R. J., Avramopoulos, D., Jantzie, L. L., & McCallion, A. S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02584-x · Cited by 162 · see citing works
Microglial amyloid beta clearance is driven by PIEZO1 channels
Jäntti, H., Sitnikova, V., Ishchenko, Y., Shakirzyanova, A., Giudice, L., Ugidos, I. F., Gómez‐Budia, M., Korvenlaita, N., Ohtonen, S., Belaya, I., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02486-y · Cited by 162 · see citing works
“Sustained exposure to Aβ, cytokines and other inflammatory mediators appear to cause permanent impairment in microglial function at the plaque sites [77] manifested by impairment in motility and phagocytosis in mice with AD phenotype [78].”
BackgroundMicroglia inflict delayed brain injury after subarachnoid hemorrhage
Schneider, U. C., Davids, A., Brandenburg, S., Müller, A., Elke, A., Magrini, S., Atangana, E. N., Turkowski, K., Finger, T., Gutenberg, A., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1440-1 · Cited by 152 · see citing works
“Microglia have been discussed to play pivotal roles in CNS pathologies like Alzheimer’s disease, autoimmune encephalomyelitis, traumatic brain injury and ischemic stroke [4, 8, 32, 38], where microglia fulfill their pleiotropic roles as cells of the innate immune system, including antigen presentation, phagocytosis an…”
BackgroundSelf-citationMicroglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets
Nizami, S., Hall‐Roberts, H., Warrier, S., Cowley, S. A., & Di Daniel, E. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14618 · Cited by 147 · see citing works
“There are a large number of factors that can contribute to the extracellular build‐ up of Aβ aggregates in AD brains, one of which may be reduced microglial phagocytosis, which is observed in rodent models (Krabbe et al., 2013).”
BackgroundMicroglial polarization: novel therapeutic mechanism against Alzheimer’s disease
Yao, K., & Zu, H. (2019) · Inflammopharmacology · doi:10.1007/s10787-019-00613-5 · Cited by 146 · see citing works
Molecular Mechanisms of Microglial Motility: Changes in Ageing and Alzheimer’s Disease
Franco-Bocanegra, D. K., McAuley, C., Nicoll, J. A. R., & Boche, D. (2019) · Cells · doi:10.3390/cells8060639 · Cited by 147 · see citing works
“In situ experiments using acute brain slices demonstrated that the speed of microglial process motility was reduced in the APPPS1 compared to control mice after a laser insult [108].”
BackgroundFibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models
Sebastian Monasor, L., Müller, S. A., Colombo, A. V., Tanrioever, G., König, J., Roth, S., Liesz, A., Berghofer, A., Piechotta, A., Prestel, M., et al. (2020) · eLife · doi:10.7554/elife.54083 · Cited by 147 · see citing works
Salminen, A. (2023) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02289-5 · Cited by 149 · see citing works
Bolton, J. L., Short, A. K., Othy, S., Kooiker, C. L., Shao, M., Gunn, B. G., Beck, J., Bai, X., Law, S. M., Savage, J. C., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110600 · Cited by 146 · see citing works
“Whereas reduced microglial process dynamics has been associated with diminished “surveillance” of neurons and blunted microglial function (Abiega et al., 2016; Damani et al., 2011; Krabbe et al., 2013), it remains unclear whether these deficits in ELA microglia abutting CRH+ neurons result in deficient synapse engulfm…”
BackgroundKorvatska, O., Leverenz, J. B., Jayadev, S., McMillan, P., Kurtz, I., Guo, X., Rumbaugh, M., Matsushita, M., Girirajan, S., Dorschner, M. O., et al. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.0979 · Cited by 137 · see citing works
Brelstaff, J. H., Mason, M., Katsinelos, T., McEwan, W. A., Ghetti, B., Tolkovsky, A. M., & Spillantini, M. G. (2021) · Science Advances · doi:10.1126/sciadv.abg4980 · Cited by 135 · see citing works
Crashing the computer: apoptosis vs. necroptosis in neuroinflammation
Heckmann, B. L., Tummers, B., & Green, D. R. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0195-3 · Cited by 132 · see citing works
Inflammatory aspects of Alzheimer’s disease
Lucena, P. B., & Heneka, M. T. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02790-2 · Cited by 143 · see citing works
“Furthermore, Aβ clearance seems to be impaired not only in late but early onset forms of AD [149, 178], and its regulation and effectiveness may depend on factors such as age or stage of the disease [122].”
Heat-Shock Proteins in Neuroinflammation
Dukay, B., Csoboz, B., & Tóth, M. E. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00920 · Cited by 132 · see citing works
“In vitro and transgenic mouse studies showed that healthy microglia can help to remove dysfunctional neuronal cells and restrain the progression of the disease (Kraft et al., 2012; Benraiss et al., 2016).”
BackgroundMicroglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain
Gu, N., Eyo, U. B., Murugan, M., Peng, J., Matta, S., Dong, H., & Wu, L. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.11.007 · Cited by 131 · see citing works
“A few factors regulating microglial surveillance have been recognised including neuronal activity in general (Fontainhas et al., 2011; Li et al., 2012; Nimmerjahn et al., 2005; Tremblay et al., 2010) as well as through specific molecules including purines (Davalos et al., 2005; Kurpius et al., 2007; Orr et al., 2009)…”
Götzl, J. K., Brendel, M., Werner, G., Parhizkar, S., Monasor, L. S., Kleinberger, G., Colombo, A.-V., Deußing, M., Wagner, M., Winkelmann, J., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809711 · Cited by 124 · see citing works
“On the other hand, during aging wild-type microglia in an AD mouse model lose their motility and phagocytic activity (Krabbe et al, 2013) although they express a neurodegenerative disease-associated mRNA profile (Krasemann et al, 2017).”
BackgroundMicroglial Malfunction: The Third Rail in the Development of Alzheimer's Disease
Mhatre, S. D., Tsai, C. A., Rubin, A. J., James, M. L., & Andreasson, K. I. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.08.006 · Cited by 134 · see citing works
“However, exposure to accumulating Ab peptides leads to loss of these crucial microglial functions, resulting in a persistent proinflammatory state and failure to clear misfolded proteins [92,93].”
Cerovic, M., Forloni, G., & Balducci, C. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00284 · Cited by 126 · see citing works
“In addition, activated microglia loses their phagocytic properties, thus reducing the degree of Aβ phagocytosis, and consequently promoting its accumulation (Krabbe et al., 2013).”
BackgroundSubramanian, J., Savage, J. C., & Tremblay, M. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.592607 · Cited by 124 · see citing works
Targeting innate immunity for neurodegenerative disorders of the central nervous system
Andreasson, K. I., Bachstetter, A. D., Colonna, M., Ginhoux, F., Holmes, C., Lamb, B., Landreth, G., Lee, D. C., Low, D., Lynch, M. A., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13667 · Cited by 126 · see citing works
Systemic inflammation regulates microglial responses to tissue damage in vivo
Gyoneva, S., Davalos, D., Biswas, D., Swanger, S. A., Garnier‐Amblard, E. C., Loth, F., Akassoglou, K., & Traynelis, S. F. (2014) · Glia · doi:10.1002/glia.22686 · Cited by 126 · see citing works
“Consistent with our findings Gyoneva et al.: Microglial Motility in LPS-Treated Mice August 2014 1357 with systemic activation, microglia in an animal model of AD, which are locally activated by the ongoing Ab pathology, also show a reduced response to laser ablation (Krabbe et al., 2013).”
BackgroundResultBoza‐Serrano, A., Yang, Y., Paulus, A., & Deierborg, T. (2018) · Scientific Reports · doi:10.1038/s41598-018-19699-y · Cited by 123 · see citing works
Teter, B., Morihara, T., Lim, G. P., Chu, T., Jones, M. R., Zuo, X., Paul, R. M., Frautschy, S. A., & Cole, G. M. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.02.015 · Cited by 125 · see citing works
“, 2002), clearance fails with chronic inflammation and the onset of amyloid plaques (Hickman et al., 2008; Krabbe et al., 2013).”
BackgroundDifferential contribution of microglia and monocytes in neurodegenerative diseases
Baufeld, C., O'Loughlin, E. K., Calcagno, N., Madore, C., & Butovsky, O. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1795-7 · Cited by 123 · see citing works
“This might be because they are impaired in their phagocytic function by the presence of Ab, chronic inflammation, or an age-linked dysfunction (Streit et al. 2004; Hickman et al. 2013; Krabbe et al. 2013).”
BackgroundInflammatory mechanisms in neurodegeneration
Nichols, M. R., St‐Pierre, M., Wendeln, A., Makoni, N. J., Gouwens, L. K., Garrad, E. C., Sohrabi, M., Neher, J. J., Tremblay, M., & Combs, C. K. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14674 · Cited by 122 · see citing works
“For example, various studies demonstrated impairments in microglial phagocytosis in AD models (Floden and Combs 2011; Krabbe et al. 2013; Wildsmith et al. 2013).”
ResultImpact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice
Prokop, S., Miller, K. R., Drost, N., Handrick, S., Mathur, V., Luo, J., Wegner, A., Wyss-Coray, T., & Heppner, F. L. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20150479 · Cited by 116 · see citing works
Self-citationUltrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology
El Hajj, H., Savage, J. C., Bisht, K., Parent, M., Vallières, L., Rivest, S., & Tremblay, M.-È. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1473-9 · Cited by 119 · see citing works
Genetic targeting of microglia
Wieghofer, P., Knobeloch, K., & Prinz, M. (2014) · Glia · doi:10.1002/glia.22727 · Cited by 116 · see citing works
“Examples include Alzheimer’s disease (AD) (Cho et al., 2011; Fuhrmann et al., 2010; Krabbe et al., 2013; Lee et al., 2010), Parkinson’s disease (PD) (Cardona et al.”
BackgroundInhomogeneous distribution of Iba‐1 characterizes microglial pathology in Alzheimer's disease
Tischer, J., Krueger, M., Mueller, W. C., Staszewski, O., Prinz, M., Streit, W. J., & Bechmann, I. (2016) · Glia · doi:10.1002/glia.23024 · Cited by 117 · see citing works
“, 1993), and a recent study demonstrates a form of paralysis of microglia near to amyloid deposits using twophoton life-imaging in APPPS1 and APP23 mice (Krabbe et al., 2013).”
BackgroundInfluential
- 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
- Health Sciences › Medicine › Physiology › 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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