Inflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models
Open accessAbstract
Microglia are the primary immune cell of the brain and function to protect the central nervous system (CNS) from injury and invading pathogens. In the homeostatic brain, microglia serve to support neuronal health through synaptic pruning, promoting normal brain connectivity and development, and through release of neurotrophic factors, providing support for CNS integrity. However, recent evidence indicates that the homeostatic functioning of these cells is lost in neurodegenerative disease, including Alzheimer's disease (AD), ultimately contributing to a chronic neuroinflammatory environment in the brain. Importantly, the development of compounds and genetic models to ablate the microglial compartment has emerged as effective tools to further our understanding of microglial function in AD. Use of these models has identified roles of microglia in several pathological facets of AD, including tau propagation, synaptic stripping, neuronal loss, and cognitive decline. Although culminating evidence utilizing these microglial ablation models reports an absence of CNS-endogenous and peripheral myeloid cell involvement in Aβ phagocytosis, recent data indicates that targeting microglia-evoked neuroinflammation in AD may be essential for potential therapeutics. Therefore, identifying altered signaling pathways in the microglia-devoid brain may assist with the development of effective inflammation-based therapies in AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Microglial responses in Alzheimer's disease are not uniformly harmful and cannot be reduced to a simple activated-versus-resting distinction.
“more recent work suggests that microglial responses in Alzheimer’s disease are not uniformly harmful and cannot be reduced to a simple activated-versus-resting distinction [13,14].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [14]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · 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
Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., et al. (2010) · Science · doi:10.1126/science.1194637 · Cited by 5,175 · see citing works
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336 · see citing works
Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., et al. (2011) · Science · doi:10.1126/science.1202529 · Cited by 4,244 · see citing works
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089 · see citing works
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · see citing works
Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326 · see citing works
NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice
Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., et al. (2013) · Nature · doi:10.1038/nature11729 · Cited by 2,898 · see citing works
Alzheimer disease in the United States (2010–2050) estimated using the 2010 census
Hebert, L. E., Weuve, J., Scherr, P. A., & Evans, D. A. (2013) · Neurology · doi:10.1212/wnl.0b013e31828726f5 · Cited by 2,642 · see citing works
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208 · see citing works
Elmore, M. R. P., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E., Rice, R. A., Kitazawa, M., Matusow, B., Nguyen, H., West, B. L., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.040 · Cited by 1,968 · see citing works
Self-citationNaj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901 · see citing works
Microglia Shape Adult Hippocampal Neurogenesis through Apoptosis-Coupled Phagocytosis
Sierra, A., Encinas, J. M., Deudero, J. J. P., Chancey, J. H., Enikolopov, G., Overstreet-Wadiche, L. S., Tsirka, S. E., & Maletic-Savatic, M. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.08.014 · Cited by 1,622 · see citing works
Microglial interactions with synapses are modulated by visual experience
Tremblay, M.-È., Lowery, R. L., & Majewska, A. K. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000527 · Cited by 1,542 · see citing works
Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions
Mildner, A., Schmidt, H., Nitsche, M., Merkler, D., Hanisch, U.-K., Mack, M., Heikenwalder, M., Brück, W., Priller, J., & Prinz, M. (2007) · Nature Neuroscience · doi:10.1038/nn2015 · Cited by 1,089 · see citing works
ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models
Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y. D., Karlo, J. C., Zinn, A. E., Casali, B. T., Restivo, J. L., Goebel, W. D., James, M. J., et al. (2012) · Science · doi:10.1126/science.1217697 · Cited by 1,050 · see citing works
Microglial Activation and Chronic Neurodegeneration
Lull, M. E., & Block, M. L. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.014 · Cited by 1,047 · see citing works
Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease
Meyer-Luehmann, M., Spires-Jones, T. L., Prada, C., Garcia-Alloza, M., de Calignon, A., Rozkalne, A., Koenigsknecht-Talboo, J., Holtzman, D. M., Bacskai, B. J., & Hyman, B. T. (2008) · Nature · doi:10.1038/nature06616 · Cited by 987 · see citing works
Saman, S., Kim, W., Raya, M., Visnick, Y., Miro, S., Saman, S., Jackson, B., McKee, A. C., Alvarez, V. E., Lee, N. C. Y., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.277061 · Cited by 985 · see citing works
Fiandaca, M. S., Kapogiannis, D., Mapstone, M., Boxer, A., Eitan, E., Schwartz, J. B., Abner, E. L., Petersen, R. C., Federoff, H. J., Miller, B. L., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.06.008 · Cited by 959 · see citing works
TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
Wang, Y., Ulland, T. K., Ulrich, J. D., Song, W., Tzaferis, J. A., Hole, J. T., Yuan, P., Mahan, T. E., Shi, Y., Gilfillan, S., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151948 · Cited by 840 · see citing works
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. (2016) · Brain · doi:10.1093/brain/aww016 · Cited by 695 · see citing works
Self-citationJay, T. R., Miller, C. M., Cheng, P. J., Graham, L. C., Bemiller, S., Broihier, M. L., Xu, G., Margevicius, D., Karlo, J. C., Sousa, G. L., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142322 · Cited by 682 · cited 4× · see citing works
“These surviving cells may be infiltrated monocytes, which are not dependent on CSF1R signaling for their survival (Jay et al., 2015), or may alternatively upregulate TREM2, which can act as a survival signal in place of CSF1R (Wang et al., 2015).”
BackgroundInfluentialRegulation of Tau Pathology by the Microglial Fractalkine Receptor
Bhaskar, K., Konerth, M., Kokiko-Cochran, O. N., Cardona, A., Ransohoff, R. M., & Lamb, B. T. (2010) · Neuron · doi:10.1016/j.neuron.2010.08.023 · Cited by 639 · see citing works
Bruttger, J., Karram, K., Wörtge, S., Regen, T., Marini, F., Hoppmann, N., Klein, M., Blank, T., Yona, S., Wolf, Y., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.06.012 · Cited by 634 · see citing works
Valdearcos, M., Robblee, M. M., Benjamin, D. I., Nomura, D. K., Xu, A. W., & Koliwad, S. K. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.11.018 · Cited by 629 · see citing works
Olmos-Alonso, A., Schetters, S. T. T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., Holscher, C., Perry, V. H., & Gomez-Nicola, D. (2016) · Brain · doi:10.1093/brain/awv379 · Cited by 532 · see citing works
Hamelin, L., Lagarde, J., Dorothée, G., Leroy, C., Labit, M., Comley, R. A., de Souza, L. C., Corne, H., Dauphinot, L., Bertoux, M., et al. (2016) · Brain · doi:10.1093/brain/aww017 · Cited by 519 · see citing works
Morris, J. C., & Price, J. L. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:17:2:101 · Cited by 513 · see citing works
Edison, P., Archer, H. A., Gerhard, A., Hinz, R., Pavese, N., Turkheimer, F. E., Hammers, A., Tai, Y. F., Fox, N., Kennedy, A., et al. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.08.001 · Cited by 513 · see citing works
Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex
Sipe, G. O., Lowery, Tremblay, M.-È., Kelly, E. A., Lamantia, C. E., & Majewska, A. K. (2016) · Nature Communications · doi:10.1038/ncomms10905 · Cited by 512 · see citing works
Shaftel, S. S., Kyrkanides, S., Olschowka, J. A., Miller, J.-N. H., Johnson, R. E., & O’Banion, M. K. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31450 · Cited by 433 · see citing works
Eimer, W. A., & Vassar, R. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-2 · Cited by 425 · cited 1× · see citing works
“Importantly, the 5xfAD mouse model is the only model of AD to date that exhibits profound neuronal loss, specifically in the subiculum and layer V cortex (Eimer and Vassar, 2013), permitting inquiries into the role of chronically activated microglia in promoting the loss of neurons.”
BackgroundFormation 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
Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice
Krstic, D., Madhusudan, A., Doehner, J., Vogel, P., Notter, T., Imhof, C., Manalastas, A., Hilfiker, M., Pfister, S., Schwerdel, C., et al. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-151 · Cited by 400 · see citing works
IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
Fu, A. K. Y., Hung, K.-W., Yuen, M. Y. F., Zhou, X., Mak, D. S. Y., Chan, I. C. W., Cheung, T. H., Zhang, B., Fu, W.-Y., Liew, F. Y., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604032113 · Cited by 369 · see citing works
NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes
Gustin, A., Kirchmeyer, M., Koncina, E., Felten, P., Losciuto, S., Heurtaux, T., Tardivel, A., Heuschling, P., & Dostert, C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0130624 · Cited by 369 · see citing works
Alternative activation of macrophages: immune function and cellular biology
Varin, A., & Gordon, S. (2009) · Immunobiology · doi:10.1016/j.imbio.2008.11.009 · Cited by 361 · see citing works
Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial
ADAPT Research Group (2007) · Neurology · doi:10.1212/01.wnl.0000260269.93245.d2 · Cited by 354 · 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 · cited 1× · see citing works
“Modulation of microglial function in AD has been repeatedly shown to improve cognitive function (i.e. (Parachikova et al., 2010; Yamanaka et al., 2012)), indicating that chronically reactive microglia are promoting the cognitive decline that occurs in the disease.”
BackgroundRice, R. A., Spangenberg, E. E., Yamate-Morgan, H., Lee, R. J., Arora, R. P. S., Hernandez, M. X., Tenner, A. J., West, B. L., & Green, K. N. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0336-15.2015 · Cited by 270 · cited 7× · see citing works
“adult mice devoid of microglia compared to microglia-intact mice (Rice et al., 2015), suggesting that these cells continue to sculpt the synaptic landscape into adulthood.”
BackgroundInfluentialSelf-citationSpreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid
Nath, S., Agholme, L., Kurudenkandy, F. R., Granseth, B., Marcusson, J., & Hallbeck, M. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0615-12.2012 · Cited by 244 · see citing works
Jankowsky, 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
Intrahippocampal LPS injections reduce Aβ load in APP+PS1 transgenic mice
DiCarlo, G. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00292-5 · Cited by 223 · see citing works
Lack of Widespread BBB Disruption in Alzheimer’s Disease Models: Focus on Therapeutic Antibodies
Bien-Ly, N., Boswell, C. A., Jeet, S., Beach, T. G., Hoyte, K., Luk, W., Shihadeh, V., Ulufatu, S., Foreman, O., Lu, Y., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.036 · Cited by 198 · see citing works
Dugan, L. L., Ali, S. S., Shekhtman, G., Roberts, A. J., Lucero, J., Quick, K. L., & Behrens, M. M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005518 · Cited by 165 · 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
Genetics ignite focus on microglial inflammation in Alzheimer’s disease
Malik, M., Parikh, I., Vasquez, J. B., Smith, C., Tai, L., Bu, G., LaDu, M. J., Fardo, D. W., Rebeck, G. W., & Estus, S. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0048-1 · Cited by 161 · see citing works
Yasuno, F., Kosaka, J., Ota, M., Higuchi, M., Ito, H., Fujimura, Y., Nozaki, S., Takahashi, S., Mizukami, K., Asada, T., et al. (2012) · Psychiatry Research: Neuroimaging · doi:10.1016/j.pscychresns.2011.08.013 · Cited by 148 · see citing works
Varvel, N. H., Grathwohl, S. A., Degenhardt, K., Resch, C., Bosch, A., Jucker, M., & Neher, J. J. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20150478 · Cited by 99 · see citing works
Flagged first, then by citations
Research works printed but not linked: 72
- Akiyama H 2000 Inflammation and Alzheimer’s disease Neurobiol Aging 21 383 421 10858586 PMC3887148
- Alzheimer A Stelzmann RA Schnitzlein HN Murtagh FR 1995 An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde” Clin Anat 8 429 431 8713166
- Asai H Ikezu S Tsunoda S Medalla M Luebke J Haydar T Wolozin B Butovsky O Kügler S Ikezu T 2015 Depletion of microglia and inhibition of exosome synthesis halt tau propagation Nat Neurosci 18 1584 1593 26436904 PMC4694577
- Bellinger FP Madamba S Siggins GR 1993 Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus Brain Res 628 227 234 8313151
- Ben-Menachem-Zidon O Ben-Menahem Y Ben-Hur T Yirmiya R 2014 Intrahippocampal transplantation of neural precursor cells with transgenic overexpression of IL-1 receptor antagonist rescues memory and neurogenesis impairments in an Alzheimer’s disease model Neuropsychopharmacology 39 401 414 23954849 PMC3870779
- Blinzinger K Kreutzberg G 1968 Displacement of synaptic terminals from regenerating motoneurons by microglial cells Z Zellforsch Mikrosk Anat 85 145 157 5706753
- Bochner DN Sapp R Adelson JD Zhang S Lee H Djurisic M Syken J Dan Y Shatz CJ 2014 Blocking PirB up-regulates spines and functional synapses to unlock visual cortical plasticity and facilitate recovery from amblyopia Sci Transl Med 6 PMC4476552 25320232
- Bolmont T Haiss F Eicke D Radde R Mathis CA Klunk WE Kohsaka S Jucker M Calhoun ME 2008 Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance J Neurosci 28 4283 4292 18417708 PMC3844768
- Bornemann KD Wiederhold KH Pauli C Ermini F Stalder M Schnell L Sommer B Jucker M Staufenbiel M 2001 Aβ-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice Am J Pathol 158 63 73 11141480 PMC1850262
- Brown GC Neher JJ 2014 Microglial phagocytosis of live neurons Nat Rev Neurosci 15 209 216 24646669
- Cagnin A Brooks DJ Kennedy AM Gunn RN Myers R Turkheimer FE Jones T Banati RB 2001 In-vivo measurement of activated microglia in dementia The Lancet 358 461 467 11513911
- Chakrabarty P Li A Ceballos-Diaz C Eddy JA Funk CC Moore B DiNunno N Rosario AM Cruz PE Verbeeck C Sacino A Nix S Janus C Price ND Das P Golde TE 2015 IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior Neuron 85 519 533 25619653 PMC4320003
- Claassen I Van Rooijen N Claassen E 1990 A new method for removal of mononuclear phagocytes from heterogeneous cell populations in vitro, using the liposome-mediated macrophage ‘suicide’ technique J Immunol Methods 134 153 161 2147710
- Condello C Yuan P Schain A Grutzendler J 2015 Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques Nat Commun 6 6176 25630253 PMC4311408
- Cummings JL Zhong K Kinney JW Heaney C Moll-Tudla J Joshi A Pontecorvo M Devous M Tang A Bena J 2016 Double-blind, placebo-controlled, proof-of-concept trial of bexarotene in moderate Alzheimer’s disease Alzheimers Res Ther 8 4 26822146 PMC4731943
- Dagher NN Najafi AR Kayala KM Elmore MR White TE Medeiros R West BL Green KN 2015 Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice J Neuroinflammation 12 139 26232154 PMC4522109
- De I Nikodemova M Steffen MD Sokn E Maklakova VI Watters JJ Collier LS 2014 CSF1 overexpression has pleiotropic effects on microglia in vivo Glia 62 1955 1967 25042473 PMC4205273
- de Jong D Jansen R Hoefnagels W Jellesma-Eggenkamp M Verbeek M Borm G Kremer B 2008 No effect of one-year treatment with indomethacin on Alzheimer’s disease progression: a randomized controlled trial PLoS One 3 e1475 18213383 PMC2194921
- Ferretti MT Bruno MA Ducatenzeiler A Klein WL Cuello AC 2012 Intracellular Aβ-oligomers and early inflammation in a model of Alzheimer’s disease Neurobiol Aging 33 1329 1342 21414686
- Frautschy SA Yang F Irrizarry M Hyman B Saido TC Hsiao K Cole GM 1998 Microglial response to amyloid plaques in APPsw transgenic mice Am J Pathol 152 307 317 9422548 PMC1858113
- Fuhrmann M Bittner T Jung CK Burgold S Page RM Mitteregger G Haass C LaFerla FM Kretzschmar H Herms J 2010 Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease Nat Neurosci 13 411 413 20305648 PMC4072212
- Griciuc A Serrano-Pozo A Parrado AR Lesinski AN Asselin CN Mullin K Hooli B Choi SH Hyman BT Tanzi RE 2013 Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta Neuron 78 631 643 23623698 PMC3706457
- Guerreiro R 2013 TREM2 variants in Alzheimer’s disease N Engl J Med 368 117 127 23150934 PMC3631573
- Hebert SE Scherr PA Bienias JL Bennett DA Evans DA 2003 Alzheimer disease in the US population: prevalence estimates using the 2000 census Arch Neurol 60 1119 1122 12925369
- Hellwig S Masuch A Nestel S Katzmarski N Meyer-Luehmann M Biber K 2015 Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-beta plaque formation in organotypic hippocampal slice cultures Sci Rep 5 14624 26416689 PMC4586757
- Heneka MT Sastre M Dumitrescu-Ozimek L Dewachter I Walter J Klockgether T Van Leuven F 2005 Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice J Neuroinflammation 2 22 16212664 PMC1274341
- Hoarau JJ Krejbich-Trotot P Jaffar-Bandjee MC Das T Thon-Hon GV Kumar S Neal JW Gasque P 2011 Activation and control of CNS innate immune responses in health and diseases: a balancing act finely tuned by neuroimmune regulators (NIReg) CNS Neurol Disord Drug Targets 10 25 43 21143144
- Hollingworth P 2011 Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease Nat Genet 43 429 435 21460840 PMC3084173
- Kan MJ Lee JE Wilson JG Everhart AL Brown CM Hoofnagle AN Jansen M Vitek MP Gunn MD Colton CA 2015 Arginine deprivation and immune suppression in a mouse model of Alzheimer’s disease J Neurosci 35 5969 5982 25878270 PMC4397598
- Klein D Patzko A Schreiber D van Hauwermeiren A Baier M Groh J West BL Martini R 2015 Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice Brain 138 3193 3205 26297559
- Koenigsknecht-Talboo J Landreth GE 2005 Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines J Neurosci 25 8240 8249 16148231 PMC6725530
- Kuret J Congdon EE Li G Yin H Yu X Zhong Q 2005 Evaluating triggers and enhancers of tau fibrillization Microsc Res Tech 67 141 155 16103995
- Leinenga G Götz J 2015 Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model Sci Transl Med 7 25761889
- Li R Shen Y Yang LB Lue LF Finch C Rogers J 2000 Estrogen enhances uptake of amyloid beta-protein by microglia derived from the human cortex J Neurochem 75 1447 1454 10987824
- Lopes KO Sparks DL Streit WJ 2008 Microglial dystrophy in the aged and Alzheimer’s disease brain is associated with ferritin immunoreactivity Glia 56 1048 1060 18442088
- Maphis N Xu G Kokiko-Cochran ON Jiang S Cardona A Ransohoff RM Lamb BT Bhaskar K 2015 Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain Brain 138 1738 1755 25833819 PMC4542622
- Melah KE Lu SY Hoscheidt SM Alexander AL Adluru N Destiche DJ Carlsson CM Zetterberg H Blennow K Okonkwo OC Gleason CE Dowling NM Bratzke LC Rowley HA Sager MA Asthana S Johnson SC Bendlin BB 2016 Cerebrospinal Fluid Markers of Alzheimer’s Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer’s Disease J Alzheimers Dis 50 873 886 26836182 PMC4760877
- Mildner A Schlevogt B Kierdorf K Böttcher C Erny D Kummer MP Quinn M Brück W Bechmann I Heneka MT Priller J Prinz M 2011 Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease J Neurosci 31 11159 11171 21813677 PMC6623351
- Mintun MA Larossa GN Sheline YI Dence CS Lee SY Mach RH Klunk WE Mathis CA DeKosky ST Morris JC 2006 [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease Neurology 67 446 452 16894106
- Nelson PT Braak H Markesbery WR 2009 Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship J Neuropathol Exp Neurol 68 1 14 19104448 PMC2692822
- Pan XD Zhu YG Lin N Zhang J Ye QY Huang HP Chen XC 2011 Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer’s disease Mol Neurodegener 6 PMC3149591 21718498
- Parachikova A Vasilevko V Cribbs DH LaFerla FM Green KN 2010 Reductions in amyloid-beta-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation J Alzheimers Dis 21 527 542 20555131 PMC4085054
- Paresce DM Chung H Maxfield FR 1997 Slow Degradation of Aggregates of the Alzheimer’s Disease Amyloid b-Protein by Microglial Cells J Biol Chem 272 29390 29397 9361021
- Parkhurst CN Yang G Ninan I Savas JN Yates JR 3rd Lafaille JJ Hempstead BL Littman DR Gan WB 2013 Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor Cell 155 1596 1609 24360280 PMC4033691
- Polazzi E Monti B 2010 Microglia and neuroprotection: from in vitro studies to therapeutic applications Prog Neurobiol 92 293 315 20609379
- Prokop S Miller KR Heppner FL 2013 Microglia actions in Alzheimer’s disease Acta Neuropathologica 126 461 477 24224195
- Prokop S Miller KR Drost N Handrick S Mathur V Luo J Wegner A Wyss-Coray T Heppner FL 2015 Impact of peripheral myeloid cells on amyloid-beta pathology in Alzheimer’s disease-like mice J Exp Med 212 1811 1818 26458768 PMC4612091
- Rose SE Chen F Chalk JB Zelaya FO Strugnell WE Benson M Semple J Doddrell DM 2000 Loss of connectivity in Alzheimer’s disease: an evaluation of white matter tract integrity with colour coded MR difusion tensor imaging J Neurol Neurosurg Psychiatry 69 528 530 10990518 PMC1737121
- Sakae N 2016 ABCA7 Deficiency Accelerates Amyloid-beta Generation and Alzheimer’s Neuronal Pathology J Neurosci 36 3848 3859 27030769 PMC4812140
- Satoh K Abe-Dohmae S Yokoyama S St George-Hyslop P Fraser PE 2015 ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing J Biol Chem 290 24152 24165 26260791 PMC4591804
- Scheff SW Price DA Schmitt FA Mufson EJ 2006 Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment Neurobiol Aging 27 1372 1384 16289476
- Schreiner B Romanelli E Liberski P Ingold-Heppner B Sobottka-Brillout B Hartwig T Chandrasekar V Johannssen H Zeilhofer HU Aguzzi A Heppner F Kerschensteiner M Becher B 2015 Astrocyte Depletion Impairs Redox Homeostasis and Triggers Neuronal Loss in the Adult CNS Cell Rep 12 1377 1384 26299968
- Stalder M Deller T Staufenbiel M Jucker M 2001 3D-Reconstruction of microglia and amyloid in APP23 transgenic mice: no evidence of intracellular amyloid Neurobiol Aging 22 427 434 11378249
- Streit WJ 2002 Microglia as neuroprotective, immunocompetent cells of the CNS Glia 40 133 139 12379901
- Streit WJ Braak H Xue QS Bechmann I 2009 Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease Acta Neuropathol 118 475 485 19513731 PMC2737117
- Syken J Grandpre T Kanold PO Shatz CJ 2006 PirB Restricts Ocular-Dominance Plasticity in Visual Cortex Science 313 1795 1800 16917027
- Terrando N Monaco C Ma D Foxwell BM Feldmann M Maze M 2010 Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline Proc Natl Acad Sci U S A 107 20518 20522 21041647 PMC2996666
- Terry RD 1998 The cytoskeleton in Alzheimer disease J Neural Trasn Suppl 53 141 145 9700652
- Torres L Danver J Ji K Miyauchi JT Chen D Anderson ME West BL Robinson JK Tsirka SE 2015 Dynamic microglial modulation of spatial learning and social behavior Brain Behav Immun PMC4779430 26348580
- Town T Laouar Y Pittenger C Mori T Szekely CA Tan J Duman RS Flavell RA 2008 Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology Nat Med 14 681 687 18516051 PMC2649699
- Underhill DM Goodridge HS 2012 Information processing during phagocytosis Nat Rev Immunol 12 492 502 22699831 PMC5570470
- Versijpt JJ Dumont F Van Laere KJ Decoo D Santens P Audenaert K Achten E Slegers G Dierckx RA Korf J 2003 Assessment of Neuroinflammation and Microglial Activation in Alzheimer’s Disease with Radiolabelled PK11195 and Single Photon Emission Computed Tomography European Neurology 50 39 47 12824711
- Wang Y Szretter KJ Vermi W Gilfillan S Rossini C Cella M Barrow AD Diamond MS Colonna M 2012 IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia Nat Immunol 13 753 760 22729249 PMC3941469
- Wang Y Cella M Mallinson K Ulrich JD Young KL Robinette ML Gilfillan S Krishnan GM Sudhakar S Zinselmeyer BH Holtzman DM Cirrito JR Colonna M 2015 TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model Cell 160 1061 1071 25728668 PMC4477963
- Wegiel J Wiśniewski HM Dziewiatkowski J Tarnawski M Kozielski R Trenkner E Wiktor-Jedrzejczak W 1998 Reduced number and altered morphology of microglial cells in colony stimulating factor-1-deficient osteopetrotic op/op mice Brain Res 804 135 139 9729335
- Wegiel J Wang K Imaki H Rubenstein R Wronska A Osuchowski M Lipinski WJ Walker LC LeVine H 2001 The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APPSW mice J Neurosci 31 11159 11171 11164276
- Wohleb ES Powell ND Godbout JP Sheridan JF 2013 Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior J Neurosci 33 13820 13833 23966702 PMC3755721
- Wright AL Zinn R Hohensinn B Konen LM Beynon SB Tan RP Clark IA Abdipranoto A Vissel B 2013 Neuroinflammation and neuronal loss precede Abeta plaque deposition in the hAPP-J20 mouse model of Alzheimer’s disease PLoS One 8 e59586 23560052 PMC3613362
- Yuan P Condello C Keene CD Wang Y Bird TD Paul SM Luo W Colonna M Baddeley D Grutzendler J 2016 TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy Neuron 90 724 739 27196974 PMC4898967
- Zandi PP Anthony JC Hayden KM Mehta K Mayer L Breitner JC CCS Investigators 2002 Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study Neurology 59 880 886 12297571
- Zhan Y Paolicelli RC Sforazzini F Weinhard L Bolasco G Pagani F Vyssotski AL Bifone A Gozzi A Ragozzino D Gross CT 2014 Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior Nat Neurosci 17 400 406 24487234
- Zipp F Aktas O 2006 The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases Trends Neurosci 29 518 527 16879881
Cited by
Sorted by citations
Microglia Function in the Central Nervous System During Health and Neurodegeneration
Colonna, M., & Butovsky, O. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052358 · Cited by 2,894 · see citing works
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935 · see citing works
“In this section, we discuss how microglia can directly mediate synapse loss (Wu et al., 2015; Spangenberg and Green, 2017) and exacerbate tau pathology (Leyns and Holtzman, 2017).”
BackgroundComplement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice
Shi, Q., Chowdhury, S., Ma, R., Le, K. X., Hong, S., Caldarone, B. J., Stevens, B., & Lemere, C. A. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf6295 · Cited by 593 · see citing works
“In the brain environment undergoing injury or disease, chronic activation of microglia may contribute to synaptic degeneration and memory decline (34).”
BackgroundLiu, Q., Xi, Y., Wang, Q., Liu, J., Li, P., Meng, X., Liu, K., Chen, W., Liu, X., & Liu, Z. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.04.005 · Cited by 241 · see citing works
CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
Mancuso, R., Fryatt, G., Cleal, M., Obst, J., Pipi, E., Monzón-Sandoval, J., Ribe, E., Winchester, L., Webber, C., Nevado, A., et al. (2019) · Brain · doi:10.1093/brain/awz241 · Cited by 235 · see citing works
Brelstaff, J., Tolkovsky, A. M., Ghetti, B., Goedert, M., & Spillantini, M. G. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.072 · Cited by 195 · see citing works
Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer’s disease
Branca, C., Ferreira, E., Nguyen, T.-V., Doyle, K., Caccamo, A., & Oddo, S. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx361 · Cited by 139 · see citing works
Baligács, N., Albertini, G., Borrie, S. C., Serneels, L., Pridans, C., Balusu, S., & De Strooper, B. (2024) · Nature Communications · doi:10.1038/s41467-024-54779-w · Cited by 123 · see citing works
De Simone, A., Tumiatti, V., Andrisano, V., & Milelli, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00931 · Cited by 110 · see citing works
The effect of aged microglia on synaptic impairment and its relevance in neurodegenerative diseases
Triviño, J. J., & von Bernhardi, R. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104982 · Cited by 43 · see citing works
Dong, Y., Lu, J., Zhang, S., Chen, L., Wen, J., Wang, F., Mao, Y., Li, L., Zhang, J., Liao, S., et al. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106446 · Cited by 28 · 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
Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis?
Chmiel, J., Gawełczyk, W., Soczyńska, J., & Leszek, J. (2026) · Cells · doi:10.3390/cells15131151
- Authors
- Spangenberg, E. E., & Green, K. N.
- Corresponding author
- Green, Kim N.
- ORCID
- Green, Kim N.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 61
- Pages
- 1-11
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5218993
- OpenAlex
- W2460405435
- Cited by
- 352
- References
- 53
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 48 · 2023: 38 · 2022: 50 · 2021: 55 · 2020: 47 · 2019: 24 · 2018: 30 · 2017: 19 · 2016: 3
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1R01NS083801)
- 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
- Alzheimer's disease, microglia, neuroinflammation, tau propagation, synaptic stripping, amyloid-beta phagocytosis, myeloid cells, neurodegeneration, cognitive decline
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Inflammation, Neurons, Phagocytosis, tau Proteins, Microglia
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
