Microglia in Alzheimer’s disease: A multifaceted relationship
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting elderly people worldwide, which is mainly characterized by cerebral amyloid-beta (Aβ) plaque deposition and neurofibrillary tangle formation. The interest in microglia arose from the overwhelming experimental evidence that outlined a key role of neuroinflammation in AD pathology. Microglia constitute the powerhouse of the innate immune system in the brain. It is now widely accepted that microglia are myeloid-derived cells that infiltrate the developing brain at the early embryonic stages, and acquire a highly ramified phenotype postnatally. Microglia use these dynamic ramifications as sentinels to sense and detect any occurring alteration in brain homeostasis. Once a danger signal is detected, microglia get activated by acquiring a less ramified phenotype, and mount adequate responses that range from phagocyting cell debris to secreting inflammatory and trophic factors. Earlier reports have demonstrated, unequivocally, that microglia surround Aβ plaques and internalize Aβ microaggregates. However, the implication of these observations in AD pathology, and consequently treatment, is still a matter of debate. Nonetheless, targeting the activity of these cells constituted a convergent point in this debate. Unfortunately, the conflicting experimental findings obtained following the modulation of microglial activity in AD, further fueled the debate. This review aims at providing an overview regarding wh…
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Monocyte and monocyte-derived macrophage contributions to brain pathologies are well documented in various animal models and human disorders.
“Involvement of these cells has been shown in the development, progression and resolution of experimental autoimmune encephalitis (EAE) 20-22 , stroke 23,24 , Alzheimer's disease 25,26 and viral encephalitis 27 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [27]
Cites
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
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · 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
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
Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse
Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., et al. (1999) · Nature · doi:10.1038/22124 · Cited by 3,160 · see citing works
Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders
Zlokovic, B. V. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3114 · Cited by 2,969 · 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
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
Naj, 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
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858 · 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 Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice
Hickman, S. E., Allison, E. K., & El Khoury, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0616-08.2008 · Cited by 1,329 · cited 6× · see citing works
“However, in contrast to the early stages of AD, Aβ clearance by microglia seems very slow and ineffective in the late stages (El Khoury et al., 2007; Hickman et al., 2008).”
BackgroundInfluentialMicroglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease
Prinz, M., & Priller, J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3722 · Cited by 1,329 · see citing works
Activation of microglial cells by β-amyloid protein and interferon-γ
Meda, L., Cassatella, M. A., Szendrei, G. I., Otvos, L., Baron, P., Villalba, M., Ferrari, D., & Rossi, F. (1995) · Nature · doi:10.1038/374647a0 · Cited by 1,314 · see citing works
Microglia: new roles for the synaptic stripper
Kettenmann, H., Kirchhoff, F., & Verkhratsky, A. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.023 · Cited by 1,173 · see citing works
Microglial cell origin and phenotypes in health and disease
Saijo, K., & Glass, C. K. (2011) · Nature Reviews Immunology · doi:10.1038/nri3086 · Cited by 1,100 · 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
Regulation of innate immune responses in the brain
Rivest, S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2565 · Cited by 843 · see citing works
Self-citationTREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
Kleinberger, G., Yamanishi, Y., Suárez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009093 · Cited by 798 · see citing works
Nitric oxide and redox mechanisms in the immune response
Wink, D. A., Hines, H. B., Cheng, R. Y. S., Switzer, C. H., Flores-Santana, W., Vitek, M. P., Ridnour, L. A., & Colton, C. A. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.1010550 · Cited by 765 · see citing works
Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils
Khoury, J. E., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C., & Loike, J. D. (1996) · Nature · doi:10.1038/382716a0 · Cited by 727 · see citing works
Jay, 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
“Importantly, TREM2 depletion eliminated CD45high macrophages, which significantly reduced inflammation and ameliorated AD-like pathology in transgenic mice, thus suggesting a detrimental role of TREM2-positive macrophages in AD pathology (Jay et al., 2015).”
BackgroundInfluentialJanus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis
Sierra, A., Abiega, O., Shahraz, A., & Neumann, H. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00006 · Cited by 574 · 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 · cited 4× · see citing works
“…expression levels of TNFα and chemokine (C-C motif) ligand-2 (CCL2; i.e. monocyte chemoattractant protein-1 (MCP1)) together with an increase in IL1β gene expression (Lee et al., 2010). containing-3 (NLRP3) inflammasome is critical for IL1β maturation in response to Aβ (Zambetti et al., 2012).”
BackgroundInfluentialThe origin and cell lineage of microglia: new concepts
Chan, W. Y., Kohsaka, S., & Rezaie, P. (2007) · Brain Research Reviews · doi:10.1016/j.brainresrev.2006.11.002 · Cited by 400 · cited 3× · see citing works
“In addition, it has been proposed that microglia are derived from circulating blood monocytes, especially from the late gestational stage throughout the early postnatal stage (Chan et al., 2007).”
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
Absence of C1q Leads to Less Neuropathology in Transgenic Mouse Models of Alzheimer's Disease
Fonseca, M. I., Zhou, J., Botto, M., & Tenner, A. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0901-04.2004 · Cited by 345 · see citing works
Blood–Brain Barrier Pathology in Alzheimer's and Parkinson's Disease: Implications for Drug Therapy
Desai, B. S., Monahan, A. J., Carvey, P. M., & Hendey, B. (2007) · Cell Transplantation · doi:10.3727/000000007783464731 · Cited by 339 · 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
Real-Time In Vivo Imaging Reveals the Ability of Monocytes to Clear Vascular Amyloid Beta
Michaud, J.-P., Bellavance, M.-A., Préfontaine, P., & Rivest, S. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.10.010 · Cited by 257 · see citing works
Self-citationIntrahippocampal 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
Wisniewski, H. M., Wegiel, J., Wang, K. C., & Lach, B. (1992) · Acta Neuropathologica · doi:10.1007/bf00311383 · Cited by 221 · see citing works
Frenkel, D., Wilkinson, K., Zhao, L., Hickman, S. E., Means, T. K., Puckett, L., Farfara, D., Kingery, N. D., Weiner, H. L., & El Khoury, J. (2013) · Nature Communications · doi:10.1038/ncomms3030 · Cited by 214 · see citing works
Naert, G., & Rivest, S. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0299-11.2011 · Cited by 207 · cited 1× · see citing works
“Similar results were obtained by a genetic deletion of CCR2 in APPswe/Ps1 mice (Naert and Rivest, 2011).”
ResultChakrabarty, 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
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 · cited 2× · see citing works
“…it has been shown that microglial cell surrounding Aβ plaques express high levels of TREM2 and CD45, suggesting a peripheral origin of these cells, which have been reported to efficaciously eliminate Aβ microaggregates following retinoid X receptor (RXR) agonist treatment (Savage et al., 2015).”
BackgroundQiao, X., Cummins, D. J., & Paul, S. M. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01666.x · Cited by 119 · see citing works
Blockage of CR1 prevents activation of rodent microglia
Crehan, H., Hardy, J., & Pocock, J. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.02.003 · Cited by 98 · see citing works
Microglia in Alzheimer's Disease: It's All About Context
Weitz, T. M., & Town, T. (2012) · International Journal of Alzheimer's Disease · doi:10.1155/2012/314185 · Cited by 95 · see citing works
TREM2 enables amyloid β clearance by microglia.
Rivest, S. (2015) · Cell Research · doi:10.1038/cr.2015.37 · Cited by 34 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Microglia in physiology and disease
Wolf, S. A., Boddeke, H. W. G. M., & Kettenmann, H. (2017) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034406 · Cited by 1,426 · see citing works
Anti-inflammatory Effects of Flavonoids in Neurodegenerative Disorders
Spagnuolo, C., Moccia, S., & Russo, G. L. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.09.001 · Cited by 458 · see citing works
Nanoscale Surveillance of the Brain by Microglia via cAMP-Regulated Filopodia
Bernier, L.-P., Bohlen, C. J., York, E. M., Choi, H. B., Kamyabi, A., Dissing-Olesen, L., Hefendehl, J. K., Collins, H. Y., Stevens, B., Barres, B. A., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.010 · Cited by 211 · see citing works
Zhang, X., Wang, R., Hu, D., Sun, X., Fujioka, H., Lundberg, K., Chan, E. R., Wang, Q., Xu, R., Flanagan, M. E., et al. (2020) · Science Advances · doi:10.1126/sciadv.abb8680 · Cited by 200 · see citing works
The benefits of neuroinflammation for the repair of the injured central nervous system
Yong, H. Y. F., Rawji, K. S., Ghorbani, S., Xue, M., & Yong, V. W. (2019) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0223-3 · Cited by 190 · see citing works
Ritzel, R. M., Doran, S. J., Glaser, E. P., Meadows, V. E., Faden, A. I., Stoica, B. A., & Loane, D. J. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.02.010 · Cited by 156 · see citing works
Park, S. Y., Jin, M. L., Ko, M. J., Park, G., & Choi, Y.-W. (2016) · Neurochemical Research · doi:10.1007/s11064-016-2018-6 · Cited by 87 · see citing works
Wang, Y., Wang, M., Xu, M., Li, T., Fan, K., Yan, T., Xiao, F., Bi, K., & Jia, Y. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.06.042 · Cited by 86 · see citing works
Scholtzova, H., Do, E., Dhakal, S., Sun, Y., Liu, S., Mehta, P. D., & Wisniewski, T. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.1967-16.2016 · Cited by 82 · see citing works
Exercise-Induced Modulation of Neuroinflammation in Models of Alzheimer’s Disease
Kelly, Á. M. (2018) · Brain Plasticity · doi:10.3233/bpl-180074 · Cited by 55 · see citing works
New therapeutic avenues of MCSF for brain diseases and injuries
Pons, V., & Rivest, S. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00499 · Cited by 35 · see citing works
Self-citationKim, J.-S., Trzebanski, S., Shin, S.-H., Schori, L., Frumer Friedman, G. R., Ilani, N. C., Kadam, A., Vicario, R., Aust, O., Bugaeva, P., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115609 · Cited by 33 · see citing works
Liu, H.-J., Wang, M., Wang, Y., Shi, S., Hu, X., Zhang, D.-B., Fan, D., Mintzer, J., & Xu, P. (2025) · Cell Biomaterials · doi:10.1016/j.celbio.2025.100158 · Cited by 13 · see citing works
Xie, M., Wang, T., Feng, J., Ma, D., Feng, L., & Hao, Y. (2025) · Current Neuropharmacology · doi:10.2174/1570159x23666250225091729 · Cited by 7 · see citing works
- Authors
- ElAli, A., & Rivest, S.
- Affiliations
- Université Laval (CA)
- Centre hospitalier de l'Université Laval (CA)
- Corresponding author
- Rivest, Serge
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 55
- Pages
- 138-150
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W1090090111
- Cited by
- 134
- References
- 42
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 15 · 2023: 13 · 2022: 6 · 2021: 12 · 2020: 10 · 2019: 9 · 2018: 18 · 2017: 19 · 2016: 14 · 2015: 2
- FWCI
- 9.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes in Health Research
- 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, neuroinflammation, amyloid plaques, neurofibrillary tangles, microglial activation, microglial phagocytosis, monocytes, innate immunity, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Humans, Microglia
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