Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance
Open accessAbstract
Microglial cells aggregate around amyloid plaques in Alzheimer's disease, but, despite their therapeutic potential, various aspects of their reactive kinetics and role in plaque pathogenesis remain hypothetical. Through use of in vivo imaging and quantitative morphological measures in transgenic mice, we demonstrate that local resident microglia rapidly react to plaque formation by extending processes and subsequently migrating toward plaques, in which individual transformed microglia somata remain spatially stable for weeks. The number of plaque-associated microglia increased at a rate of almost three per plaque per month, independent of plaque volume. Larger plaques were surrounded by larger microglia, and a subset of plaques changed in size over time, with an increase or decrease related to the volume of associated microglia. Far from adopting a more static role, plaque-associated microglia retained rapid process and membrane movement at the plaque/glia interface. Microglia internalized systemically injected amyloid-binding dye at a much higher rate in the vicinity of plaques. These results indicate a role for microglia in plaque maintenance and provide a model with multiple targets for therapeutic intervention.
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Microglia can internalize fibrillar Aβ in vitro and in vivo.
“Although microglia can internalize fibrillar Aβ in vitro and in vivo”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [12]
The Introduction says microglia can phagocytose Aβ in culture, and the ‘Microglia uptake of injected dye’ section reports Aβ-positive particles inside microglia in vivo. But the Discussion explicitly says further study is needed to determine whether the internalized material is soluble Aβ or fibrillary amyloid. The source therefore supports Aβ uptake in both settings, not the claim that fibrillar Aβ is internalized in vivo. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredEither deposition of Aβ itself or secondary metabolic or inflammatory events lead to progressive impairment of microglial clearance function.
“suggesting that either the deposition of A itself or secondary metabolic or inflammatory events lead to a progressive impairment of microglial clearance function.”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Bolmont et al., 2008
The Discussion (page unavailable in our copy) says the microglial response is ultimately inefficient at clearing existing amyloid deposits. It does not show a progressive decline in clearance function or identify Aβ deposition, metabolic events, or inflammation as its cause; the Discussion instead describes ongoing phagocytic activity. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMicroglia exhibit an increasing capacity for Aβ phagocytosis as Aβ adopts protofibrillar conformations but fail to phagocytose fibrillar deposits in vivo.
“Thus, the long-term persistence of methoxy-XO4 and Aβ42 (HiLyte)-555 plaque labeling coupled with the absence of TS label inside microglia strongly suggests that little phagocytosis of fibrillar amyloid takes place in vivo.”
From CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis (2010) · cites this paper as Bolmont et al., 2008
The Discussion (page unavailable) proposes that microglia may phagocytose protofibrils at plaque edges, but does not report increasing phagocytic capacity as Aβ changes conformation. It also says further study is needed to determine whether the material taken up is soluble or fibrillar Aβ, so it does not establish that microglia fail to phagocytose fibrillar deposits in vivo. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn the AD brain, microglia accumulate at the site of newly formed Aβ deposits via migration or local proliferation and may help restrict plaque growth.
“In the AD brain, microglia accumulate at the site of newly formed A deposits via migration or local proliferation and may help restrict plaque growth.4,5”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [4]
The Microglial migration and Discussion sections report movement toward new plaques and an increase in plaque-associated microglia; the Discussion offers cell division as one possible source of additional cells, rather than demonstrating local proliferation. The Discussion also finds that plaques with less microglial coverage tended to grow, consistent with the hedged suggestion that microglia may restrict growth. These observations come from transgenic mice, so the claim's unqualified reference to the AD brain extends beyond the studied setting. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia are brain-resident innate immune effector cells and are widely thought to be the key mediators of amyloid beta clearance.
“Microglia are brain-resident innate immune effector cells and are widely thought to be the key mediators of amyloid beta clearance [14–16].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [14]
The Introduction describes microglia reacting to brain injury and phagocytosing amyloid beta, and the Discussion reports that they can take up amyloid in vivo. But the paper calls their role in clearance controversial and says their response is inefficient at clearing existing deposits without additional manipulation. It does not establish resident microglia as the key mediators of amyloid beta clearance. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Microglia migrate to amyloid plaques and may alter plaque growth dynamics in transgenic mouse models of AD.
“More recent studies in transgenic mouse models of AD have shown that microglia migrate to amyloid plaques and may alter plaque growth dynamics (9–12).”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [12]
Amyloid fibrils may not be effectively degraded by microglia.
“amyloid fibrils may not be effectively degraded (8, 12).”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [12]
Microglia are inefficient in removing fibrillar Aβ.
“Experimental evidence, however, found that they are inefficient in removing fibrillar A (Bolmont et al., 2008)”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Bolmont et al., 2008
ApoE binds Aβ and is found in abundance within Aβ plaques.
“Regarding Aβ plaques, apoE is integral to plaque dynamics. 57 , 58 ApoE binds Aβ and is found in abundance within Aβ plaques.”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [57]
The Introduction and the ‘Microglia uptake of injected dye’ section discuss Aβ plaques and microglial uptake of Aβ, but do not address ApoE. Searches for ‘ApoE’ and ‘apolipoprotein E’ found no passage establishing that ApoE binds Aβ or is abundant within plaques. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · see citing works
ATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913 · see citing works
Bard, F., Cannon, C., Barbour, R., Burke, R.-L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., et al. (2000) · Nature Medicine · doi:10.1038/78682 · Cited by 2,012 · see citing works
Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease
Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S., & Selkoe, D. (1989) · Journal of Neuroimmunology · doi:10.1016/0165-5728(89)90115-x · Cited by 940 · see citing works
Spires, T. L., Meyer-Luehmann, M., Stern, E. A., McLean, P. J., Skoch, J., Nguyen, P. T., Bacskai, B. J., & Hyman, B. T. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1879-05.2005 · Cited by 550 · cited 2× · see citing works
“To facilitate repeated imaging of the same sites in the quantitative studies, Texas Red dextran (70,000 Da molecular weight; 12.5 mg/ml in sterile PBS; Invitrogen, Carlsbad, CA) was injected intravenously immediately before imaging, providing a fluorescent angiogram (Spires et al., 2005).”
MethodInfluentialMicroglia and inflammatory mechanisms in the clearance of amyloid β peptide
Rogers, J., Strohmeyer, R., Kovelowski, C. J., & Li, R. (2002) · Glia · doi:10.1002/glia.10153 · Cited by 381 · see citing works
Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice
Stalder, M., Phinney, A., Probst, A., Sommer, B., Staufenbiel, M., & Jucker, M. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65423-5 · Cited by 345 · see citing works
Self-citationJankowsky, J. L., Slunt, H. H., Gonzales, V., Savonenko, A. V., Wen, J. C., Jenkins, N. A., Copeland, N. G., Younkin, L. H., Lester, H. A., Younkin, S. G., et al. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020355 · Cited by 237 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226 · see citing works
Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253 · see citing works
Inflammation in obesity, diabetes, and related disorders
Rohm, T. V., Meier, D. T., Olefsky, J. M., & Donath, M. Y. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.013 · Cited by 2,066 · see citing works
Inflammation in Alzheimer Disease--A Brief Review of the Basic Science and Clinical Literature
Wyss-Coray, T., & Rogers, J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006346 · Cited by 975 · see citing works
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988 · see citing works
“When microglia recognize the insults of the CNS, they respond to the injury or invasion by a morphological change, resulting in cell enlargement and migration.(165) In the development of AD, it has been suggested that Aβ aggregates are the primary driver to activate microglia and set them into motion.”
BackgroundPan, R.-Y., He, L., Zhang, J., Liu, X., Liao, Y., Gao, J., Liao, Y., Yan, Y., Li, Q., Zhou, X., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.02.013 · Cited by 862 · see citing works
The role of microglia in amyloid clearance from the AD brain
Lee, C. Y. D., & Landreth, G. E. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0433-4 · Cited by 701 · see citing works
New insights on the role of microglia in synaptic pruning in health and disease
Hong, S., Dissing-Olesen, L., & Stevens, B. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2015.12.004 · Cited by 557 · see citing works
Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease
Fuhrmann, M., Bittner, T., Jung, C. K. E., Burgold, S., Page, R. M., Mitteregger, G., Haass, C., LaFerla, F. M., Kretzschmar, H., & Herms, J. (2010) · Nature Neuroscience · doi:10.1038/nn.2511 · Cited by 562 · see citing works
Lee, S., Varvel, N. H., Konerth, M. E., Xu, G., Cardona, A. E., Ransohoff, R. M., & Lamb, B. T. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.100265 · Cited by 539 · 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
“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.”
BackgroundMicroglia use TAM receptors to detect and engulf amyloid β plaques
Huang, Y., Happonen, K. E., Burrola, P. G., O’Connor, C., Hah, N., Huang, L., Nimmerjahn, A., & Lemke, G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00913-5 · Cited by 483 · see citing works
TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation
Liu, S., Liu, Y., Hao, W., Wolf, L., Kiliaan, A. J., Penke, B., Rübe, C. E., Walter, J., Heneka, M. T., Hartmann, T., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1101121 · Cited by 439 · 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
Microglia Mediate the Clearance of Soluble Aβ through Fluid Phase Macropinocytosis
Mandrekar, S., Jiang, Q., Lee, C. Y. D., Koenigsknecht-Talboo, J., Holtzman, D. M., & Landreth, G. E. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5572-08.2009 · Cited by 415 · see citing works
Capiralla, H., Vingtdeux, V., Zhao, H., Sankowski, R., Al‐Abed, Y., Davies, P., & Marambaud, P. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07594.x · Cited by 426 · 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
Self-citationJimenez, S., Baglietto-Vargas, D., Caballero, C., Moreno-Gonzalez, I., Torres, M., Sanchez-Varo, R., Ruano, D., Vizuete, M., Gutierrez, A., & Vitorica, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3024-08.2008 · Cited by 383 · see citing works
“In this sense, Bolmont et al. (2008) have recently demonstrated the internalization of A peptides by plaque-associated microglia and proposed an active role in the maintenance of plaque size.”
BackgroundA Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease
Hampel, H., Caraci, F., Cuello, A. C., Caruso, G., Nisticò, R., Corbo, M., Baldacci, F., Toschi, N., Garaci, F., Chiesa, P. A., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00456 · Cited by 360 · see citing works
“Microglia eliminate Aβ peptides and dying/dead cells through phagocytosis (59, 60).”
BackgroundMandrekar-Colucci, S., Karlo, J. C., & Landreth, G. E. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5268-11.2012 · Cited by 355 · see citing works
“Bolmont et al. (2008) have shown that microglia in the AD brain are capable of taking up Aβs and delivering them to lysosomal compartments.”
BackgroundChakrabarty, P., Jansen‐West, K., Beccard, A., Ceballos‐Diaz, C., Levites, Y., Verbeeck, C., Zubair, A. C., Dickson, D., Golde, T. E., & Das, P. (2010) · The FASEB Journal · doi:10.1096/fj.09-141754 · Cited by 328 · see citing works
Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity
Gomez-Nicola, D., & Perry, V. H. (2015) · The Neuroscientist · doi:10.1177/1073858414530512 · Cited by 340 · see citing works
Njie, E. G., Boelen, E., Stassen, F. R., Steinbusch, H. W. M., Borchelt, D. R., & Streit, W. J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.05.008 · Cited by 335 · see citing works
Yamanaka, M., Ishikawa, T., Griep, A., Axt, D., Kummer, M. P., & Heneka, M. T. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1569-12.2012 · Cited by 326 · see citing works
Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice
Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., et al. (2013) · The FASEB Journal · doi:10.1096/fj.12-208660 · Cited by 324 · see citing works
Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2
Ulrich, J. D., Finn, M. B., Wang, Y., Shen, A., Mahan, T. E., Jiang, H., Stewart, F. R., Piccio, L., Colonna, M., & Holtzman, D. M. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-20 · Cited by 302 · see citing works
Liu, Z., Condello, C., Schain, A., Harb, R., & Grutzendler, J. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4403-10.2010 · Cited by 276 · see citing works
“Previous in vivo results range from showing that microglia are effective at phagocytosis of fibrillar amyloid (Frautschy et al., 1991; Bacskai et al., 2002; Bolmont et al., 2008) to suggesting that microglia play no role in the control of amyloid deposition (Grathwohl et al., 2009).”
BackgroundResultMicroglial Aβ Receptors in Alzheimer’s Disease
Yu, Y., & Ye, R. D. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-014-0101-6 · Cited by 247 · see citing works
Baik, S. H., Kang, S., Son, S. M., & Mook-Jung, I. (2016) · Glia · doi:10.1002/glia.23074 · Cited by 234 · see citing works
Serrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182933788 · Cited by 226 · see citing works
Behrendt, G., Baer, K., Buffo, A., Curtis, M. A., Faull, R. L., Rees, M. I., Götz, M., & Dimou, L. (2013) · Glia · doi:10.1002/glia.22432 · Cited by 219 · see citing works
Naert, G., & Rivest, S. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0299-11.2011 · Cited by 207 · see citing works
“Microglia are known to react quickly to A production and subsequently migrate toward plaques (Bolmont et al., 2008).”
BackgroundChakrabarty, P., Ceballos-Diaz, C., Beccard, A., Janus, C., Dickson, D., Golde, T. E., & Das, P. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903382 · Cited by 206 · see citing works
Fu, H., Liu, B., Frost, J. L., Hong, S., Jin, M., Ostaszewski, B., Shankar, G. M., Costantino, I. M., Carroll, M. C., Mayadas, T. N., et al. (2012) · Glia · doi:10.1002/glia.22331 · Cited by 180 · see citing works
Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease
Dionisio-Santos, D. A., Olschowka, J. A., & O’Banion, M. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1453-0 · Cited by 184 · see citing works
Terwel, D., Steffensen, K. R., Verghese, P. B., Kummer, M. P., Gustafsson, J.-Å., Holtzman, D. M., & Heneka, M. T. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6546-10.2011 · Cited by 181 · see citing works
Young 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
Mechanisms of microglia accumulation in Alzheimer’s disease: therapeutic implications
Khoury, J. E., & Luster, A. D. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.08.004 · Cited by 171 · see citing works
TREM2 Function in Alzheimer’s Disease and Neurodegeneration
Ulrich, J. D., & Holtzman, D. M. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00313 · Cited by 154 · see citing works
Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease
Zhao, R., Hu, W., Tsai, J., Li, W., & Gan, W.-B. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0188-6 · Cited by 151 · see citing works
Koenigsknecht-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 · see citing works
Post-mortem analysis of neuroinflammatory changes in human Alzheimer’s disease
Gomez-Nicola, D., & Boche, D. (2015) · Alzheimer's Research & Therapy · doi:10.1186/s13195-015-0126-1 · Cited by 147 · see citing works
Differential cell proliferation in the cortex of the appsweps1de9 alzheimer's disease mouse model
Kamphuis, W., Orre, M., Kooijman, L., Dahmen, M., & Hol, E. M. (2012) · Glia · doi:10.1002/glia.22295 · Cited by 137 · see citing works
The endocytic pathway in microglia during health, aging and Alzheimer’s disease
Solé-Domènech, S., Cruz, D. L., Capetillo-Zarate, E., & Maxfield, F. R. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.07.002 · Cited by 133 · see citing works
Kummer, M. P., Ising, C., Kummer, C., Sarlus, H., Griep, A., Vieira‐Saecker, A., Schwartz, S., Halle, A., Brückner, M., Händler, K., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2021108662 · Cited by 127 · see citing works
Nuclear receptors as therapeutic targets for Alzheimer's disease
Mandrekar-Colucci, S., & Landreth, G. E. (2011) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.594043 · Cited by 126 · see citing works
Xue, X., Wang, L.-R., Sato, Y., Jiang, Y., Berg, M., Yang, D.-S., Nixon, R. A., & Liang, X.-J. (2014) · Nano Letters · doi:10.1021/nl501839q · Cited by 125 · see citing works
APOE genotype and sex affect microglial interactions with plaques in Alzheimer’s disease mice
Stephen, T. L., Cacciottolo, M., Balu, D., Morgan, T. E., LaDu, M. J., Finch, C. E., & Pike, C. J. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0729-z · Cited by 115 · see citing works
Imaging of microglia in patients with neurodegenerative disorders
Politis, M. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00096 · Cited by 111 · see citing works
High resolution dissection of reactive glial nets in Alzheimer’s disease
Bouvier, D. S., Jones, E. V., Quesseveur, G., Davoli, M. A., A. Ferreira, T., Quirion, R., Mechawar, N., & Murai, K. K. (2016) · Scientific Reports · doi:10.1038/srep24544 · Cited by 111 · see citing works
Golde, T. E., & Miller, V. M. (2009) · Alzheimer's Research & Therapy · doi:10.1186/alzrt5 · Cited by 98 · see citing works
Inflammation in transgenic mouse models of neurodegenerative disorders
Schwab, C., Klegeris, A., & McGeer, P. L. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.10.013 · Cited by 97 · see citing works
Microglia communication: parallels between aging and Alzheimer's disease
Udeochu, J. C., Shea, J. M., & Villeda, S. A. (2016) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12307 · Cited by 87 · see citing works
Marlatt, M. W., Bauer, J., Aronica, E., van Haastert, E. S., Hoozemans, J. J. M., Joels, M., & Lucassen, P. J. (2014) · Neural Plasticity · doi:10.1155/2014/693851 · Cited by 83 · see citing works
“Microglia are broadly implicated in AD [4, 8, 19] and have, for example, been found to migrate to A 𝛽 lesions 2 Neural Plasticity [20–23], degrade A 𝛽 peptide in vitro [24, 25], and participate in the clearance of A 𝛽 from the brain [26].”
BackgroundResting State fMRI Reveals Diminished Functional Connectivity in a Mouse Model of Amyloidosis
Shah, D., Jonckers, E., Praet, J., Vanhoutte, G., Delgado y Palacios, R., Bigot, C., D’Souza, D. V., Verhoye, M., & Van der Linden, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0084241 · Cited by 82 · see citing works
Rivera-Escalera, F., Pinney, J. J., Owlett, L., Ahmed, H., Thakar, J., Olschowka, J. A., Elliott, M. R., & O’Banion, M. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1645-7 · Cited by 75 · see citing works
In vivo imaging reveals sigmoidal growth kinetic of β-amyloid plaques
Burgold, S., Filser, S., Dorostkar, M. M., Schmidt, B., & Herms, J. (2014) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-2-30 · Cited by 59 · see citing works
The role of glial autophagy in Alzheimer’s disease
Litwiniuk, A., Juszczak, G. R., Stankiewicz, A. M., & Urbańska, K. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02242-5 · Cited by 54 · see citing works
Ugolini, F., Lana, D., Nardiello, P., Nosi, D., Pantano, D., Casamenti, F., & Giovannini, M. G. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00372 · Cited by 50 · see citing works
Two-Photon Imaging of Microglia in the Mouse Cortex In Vivo
Nimmerjahn, A. (2012) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot069294 · Cited by 38 · see citing works
Henningfield, C. M., Arreola, M. A., Soni, N., Spangenberg, E. E., & Green, K. N. (2022) · Glia · doi:10.1002/glia.24105 · Cited by 40 · see citing works
Gamache, J., Gingerich, D., Shwab, E. K., Barrera, J., Garrett, M. E., Hume, C., Crawford, G. E., Ashley-Koch, A. E., & Chiba-Falek, O. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01120-5 · Cited by 20 · see citing works
Tate, M., Wijeratne, H. R. S., Kim, B., Philtjens, S., You, Y., Lee, D., Gutierrez, D. A., Sharify, D., Wells, M., Perez‐Cardelo, M., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14243 · Cited by 16 · see citing works
“57,58 ApoE binds A β and is found in abundance within A β plaques.”
Crowe, S. E., & Ellis‐Davies, G. C. R. (2013) · Journal of Comparative Neurology · doi:10.1002/cne.23306 · Cited by 15 · see citing works
Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis
Walsh, A. E., Davis, B. A., Samuels, J. D., Mills, W. A., Thanos, J. M., Johnson, A. M., Moore, K. A., Puchalski, M. A., Steacy, E. J., Wendell, B. W., et al. (2026) · Journal of Experimental Medicine · doi:10.1084/jem.20260104
- Authors
- Bolmont, T., Haiss, F., Eicke, D., Radde, R., Mathis, C. A., Klunk, W. E., Kohsaka, S., Jucker, M., & Calhoun, M. E.
- Affiliations
- Hertie Institute for Clinical Brain Research (DE)
- University of Pittsburgh (US)
- National Institute of Neuroscience (JP)
- Corresponding author
- Calhoun, Michael E.
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-04-16
- Volume
- 28
- Issue
- 16
- Pages
- 4283-4292
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3844768
- OpenAlex
- W2052652421
- Cited by
- 526
- References
- 9
- Citations by year
- 2026: 11 · 2025: 31 · 2024: 60 · 2023: 39 · 2022: 34 · 2021: 37 · 2020: 31 · 2019: 28 · 2018: 21 · 2017: 18 · 2016: 22 · 2015: 21 · 2014: 32 · 2013: 34 · 2012: 31
- FWCI
- 16.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- University of Pittsburgh
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute on Aging (AG0011039, R01AG020226, AG020226)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglia, amyloid plaques, Alzheimer's disease, microglial migration, plaque-associated microglia, plaque size, transgenic mouse model
- MeSH terms
- Amyloid, Animals, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Time Factors, Microglia, Mice, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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