Microglial phagocytosis in aging and Alzheimer's disease
Abstract
Microglia are the innate immune cells of the brain, which maintain homeostasis by constantly scanning and surveying the environment with their highly ramified processes. In order to exert this function, they need to phagocytose synapses as well as debris and dead cells, a process that is further amplified in pathological conditions. Importantly, it has been shown that microglia phagocytic capacity is altered in the course of neurodegenerative disease, for which aging is one of the highest risk factors. Thus, understanding how phagocytosis is impaired during aging is a priority for future research. Advances in this area are expected to significantly contribute to our understanding of normal cognition during aging, as well as changes that take place in age-associated neurodegenerative diseases. In this review, we will summarize the current knowledge on how phagocytosis is executed and affected by aging or in age-associated neurological disorders, such as Alzheimer's disease (AD). Furthermore, we will summarize both protective and deleterious consequences of altered phagocytosis in AD and where relevant in other neurodegenerative diseases.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Autophagy and microglial phagocytosis are impaired in AD and aged brains.
“Extensive evidence shows that autophagy and microglial phagocytosis are impaired in AD and aged brains [24, 30, 94, 103].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [30]
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
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · 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
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
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
Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543 · see citing works
RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease
Yan, S. D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., et al. (1996) · Nature · doi:10.1038/382685a0 · Cited by 2,012 · 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
Transmission and spreading of tauopathy in transgenic mouse brain
Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1901 · Cited by 1,803 · see citing works
M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination
Miron, V. E., Boyd, A., Zhao, J.-W., Yuen, T. J., Ruckh, J. M., Shadrach, J. L., van Wijngaarden, P., Wagers, A. J., Williams, A., Franklin, R. J. M., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3469 · Cited by 1,788 · 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
Control of microglial neurotoxicity by the fractalkine receptor
Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1715 · Cited by 1,531 · see citing works
Identification of a factor that links apoptotic cells to phagocytes
Hanayama, R., Tanaka, M., Miwa, K., Shinohara, A., Iwamatsu, A., & Nagata, S. (2002) · Nature · doi:10.1038/417182a · Cited by 1,401 · 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 · see citing works
Microglia 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
Ageing, neurodegeneration and brain rejuvenation
Wyss-Coray, T. (2016) · Nature · doi:10.1038/nature20411 · Cited by 1,147 · see citing works
Takahashi, K., Rochford, C. D. P., & Neumann, H. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041611 · Cited by 1,124 · see citing works
TREM2 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
Myelin Impairs CNS Remyelination by Inhibiting Oligodendrocyte Precursor Cell Differentiation
Kotter, M. R., Li, W.-W., Zhao, C., & Franklin, R. J. M. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2615-05.2006 · Cited by 768 · see citing works
Microglia Promote the Death of Developing Purkinje Cells
Marı́n-Teva, J. L., Dusart, I., Colin, C., Gervais, A., van Rooijen, N., & Mallat, M. (2004) · Neuron · doi:10.1016/s0896-6273(04)00069-8 · Cited by 757 · see citing works
Chaudhuri, J., Bains, Y., Guha, S., Kahn, A., Hall, D., Bose, N., Gugliucci, A., & Kapahi, P. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.08.014 · Cited by 669 · cited 1× · see citing works
“AGEs accumulate during normal aging and in AD, diabetes, atherosclerosis or chronic kidney disease; their binding to RAGE causes inflammation and oxidative damage (Chaudhuri et al., 2018).”
BackgroundRejuvenation of Regeneration in the Aging Central Nervous System
Ruckh, J. M., Zhao, J.-W., Shadrach, J. L., van Wijngaarden, P., Rao, T. N., Wagers, A. J., & Franklin, R. J. M. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2011.11.019 · Cited by 649 · see citing works
Aging-induced type I interferon response at the choroid plexus negatively affects brain function
Baruch, K., Deczkowska, A., David, E., Castellano, J. M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., et al. (2014) · Science · doi:10.1126/science.1252945 · Cited by 615 · see citing works
Age-related myelin degradation burdens the clearance function of microglia during aging
Safaiyan, S., Kannaiyan, N., Snaidero, N., Brioschi, S., Biber, K., Yona, S., Edinger, A. L., Jung, S., Rossner, M. J., & Simons, M. (2016) · Nature Neuroscience · doi:10.1038/nn.4325 · Cited by 604 · see citing works
Inefficient clearance of myelin debris by microglia impairs remyelinating processes
Lampron, A., Larochelle, A., Laflamme, N., Préfontaine, P., Plante, M.-M., Sánchez, M. G., Yong, V. W., Stys, P. K., Tremblay, M.-È., & Rivest, S. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20141656 · Cited by 595 · see citing works
Janus-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
TREM2 sustains microglial expansion during aging and response to demyelination
Poliani, P. L., Wang, Y., Fontana, E., Robinette, M. L., Yamanishi, Y., Gilfillan, S., & Colonna, M. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77983 · Cited by 525 · see citing works
Leyns, C. E. G., Ulrich, J. D., Finn, M. B., Stewart, F. R., Koscal, L. J., Remolina Serrano, J., Robinson, G. O., Anderson, E., Colonna, M., & Holtzman, D. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710311114 · Cited by 517 · cited 3× · see citing works
“Finally, it has been suggested that TREM‐2 could also have a role in phagoptosis, by favoring the phagocytosis of stressed viable neurons in a tauopathy mouse model (Leyns et al., 2017).”
BackgroundResultLoss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts
Paloneva, J., Kestilä, M., Wu, J., Salminen, A., Böhling, T., Ruotsalainen, V., Hakola, P., Bakker, A. B. H., Phillips, J. H., Pekkarinen, P., et al. (2000) · Nature Genetics · doi:10.1038/77153 · Cited by 460 · see citing works
Coraci, I. S., Husemann, J., Berman, J. W., Hulette, C., Dufour, J. H., Campanella, G. K., Luster, A. D., Silverstein, S. C., & El Khoury, J. B. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64354-4 · Cited by 398 · see citing works
Lucin, K. M., O’Brien, C. E., Bieri, G., Czirr, E., Mosher, K. I., Abbey, R. J., Mastroeni, D. F., Rogers, J., Spencer, B., Masliah, E., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.046 · Cited by 374 · see citing works
Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death
Neher, J. J., Neniskyte, U., Zhao, J.-W., Bal-Price, A., Tolkovsky, A. M., & Brown, G. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003600 · Cited by 373 · see citing works
Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling
Gorman, A. M. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00402.x · Cited by 362 · see citing works
TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury
Mazaheri, F., Snaidero, N., Kleinberger, G., Madore, C., Daria, A., Werner, G., Krasemann, S., Capell, A., Trümbach, D., Wurst, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201743922 · Cited by 351 · see citing works
Fang, F., Lue, L.-F., Yan, S., Xu, H., Luddy, J. S., Chen, D., Walker, D. G., Stern, D. M., Yan, S., Schmidt, A. M., et al. (2010) · The FASEB Journal · doi:10.1096/fj.09-139634 · Cited by 335 · see citing works
TREM2 regulates microglial cell activation in response to demyelination in vivo
Cantoni, C., Bollman, B., Licastro, D., Xie, M., Mikesell, R., Schmidt, R., Yuede, C. M., Galimberti, D., Olivecrona, G., Klein, R. S., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1388-1 · Cited by 296 · see citing works
Dendritic Tau in Alzheimer’s Disease
Ittner, A., & Ittner, L. M. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.003 · Cited by 278 · see citing works
Lyons, A., Downer, E. J., Crotty, S., Nolan, Y. M., Mills, K. H. G., & Lynch, M. A. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.1781-07.2007 · Cited by 258 · see citing works
Absence of CX3CR1 impairs the internalization of Tau by microglia
Bolós, M., Llorens-Martín, M., Perea, J. R., Jurado-Arjona, J., Rábano, A., Hernández, F., & Avila, J. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0200-1 · Cited by 231 · 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
MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells
Healy, L. M., Perron, G., Won, S.-Y., Michell-Robinson, M. A., Rezk, A., Ludwin, S. K., Moore, C. S., Hall, J. A., Bar-Or, A., & Antel, J. P. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1502562 · Cited by 174 · see citing works
Amyloid-β-Induced Astrocytic Phagocytosis is Mediated by CD36, CD47 and RAGE
Jones, R. S., Minogue, A. M., Connor, T. J., & Lynch, M. A. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9427-3 · Cited by 147 · see citing works
Microglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
Condello, C., Yuan, P., & Grutzendler, J. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.007 · Cited by 131 · see citing works
Yang, D.-S., Stavrides, P., Saito, M., Kumar, A., Rodriguez-Navarro, J. A., Pawlik, M., Huo, C., Walkley, S. U., Saito, M., Cuervo, A. M., et al. (2014) · Brain · doi:10.1093/brain/awu278 · Cited by 114 · see citing works
Claude, J., Linnartz-Gerlach, B., Kudin, A. P., Kunz, W. S., & Neumann, H. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.2211-13.2013 · Cited by 98 · see citing works
Ricciarelli, R., d'Abramo, C., Zingg, J.-M., Giliberto, L., Markesbery, W., Azzi, A., Marinari, U. M., Pronzato, M. A., & Tabaton, M. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.01.007 · Cited by 66 · see citing works
Etchegaray, J. I., Elguero, E. J., Tran, J. A., Sinatra, V., Feany, M. B., & McCall, K. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1912-15.2016 · Cited by 55 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Antignano, I., Liu, Y., Offermann, N., & Capasso, M. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04775-y · Cited by 117 · see citing works
Self-citationSun, G. G., Wang, C., Mazzarino, R. C., Perez-Corredor, P. A., Davtyan, H., Blurton-Jones, M., Lopera, F., Arboleda-Velasquez, J. F., & Shi, Y. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114982 · Cited by 36 · see citing works
Ernest James Phillips, T., & Maguire, E. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.652593 · Cited by 33 · see citing works
Cryo‐EM structures of human ABCA7 provide insights into its phospholipid translocation mechanisms
Le, L. T. M., Thompson, J. R., Dehghani‐Ghahnaviyeh, S., Pant, S., Dang, P. X., French, J. B., Kanikeyo, T., Tajkhorshid, E., & Alam, A. (2023) · The EMBO Journal · doi:10.15252/embj.2022111065 · Cited by 31 · see citing works
Jury-Garfe, N., Redding-Ochoa, J., You, Y., Martínez, P., Karahan, H., Chimal-Juárez, E., Johnson, T. S., Zhang, J., Resnick, S., Kim, J., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02775-1 · Cited by 22 · see citing works
“Extensive evidence shows that autophagy and microglial phagocytosis are impaired in AD and aged brains [24, 30, 94, 103].”
BackgroundNon-invasive in vivo imaging of brain and retinal microglia in neurodegenerative diseases
Etebar, F., Harkin, D. G., White, A. R., & Dando, S. J. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1355557 · Cited by 7 · see citing works
- Authors
- Gabandé‐Rodríguez, E., Keane, L., & Capasso, M.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Gabandé‐Rodríguez, Enrique
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2019-04-03
- Volume
- 98
- Issue
- 2
- Pages
- 284-298
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W2925620762
- Cited by
- 127
- References
- 48
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 18 · 2023: 30 · 2022: 13 · 2021: 18 · 2020: 14 · 2019: 2
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- microglia, phagocytosis, aging, Alzheimer's disease, neurodegenerative diseases, innate immunity, brain homeostasis, cognitive aging, neuroinflammation
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain, Humans, Phagocytosis, 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
