Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology
Open accessAbstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by the deposition of extracellular fibrillar amyloid β (fΑβ) and the intracellular accumulation of neurofibrillary tangles. As AD progresses, Aβ drives a robust and prolonged inflammatory response via its recognition by microglia, the brain’s immune cells. Microglial reactivity to fAβ plaques may impair their normal surveillance duties, facilitating synaptic loss and neuronal death, as well as cognitive decline in AD. In the current study, we performed correlative light, transmission, and scanning electron microscopy to provide insights into microglial structural and functional heterogeneity. We analyzed microglial cell bodies and processes in areas containing fAβ plaques and neuronal dystrophy, dystrophy only, or appearing healthy, among the hippocampus CA1 of 14-month-old APPSwe-PS1Δe9 mice versus wild-type littermates. Our quantitative analysis revealed that microglial cell bodies in the AD model mice were larger and displayed ultrastructural signs of cellular stress, especially nearby plaques. Microglial cell bodies and processes were overall less phagocytic in AD model mice. However, they contained increased fibrillar materials and non-empty inclusions proximal to plaques. Microglial cell bodies and processes in AD model mice also displayed reduced association with extracellular space pockets that contained debris. In addition, microglial processes in healthy subregions of AD model mice encircled synaptic elements more often compared with plaque-associated processes. These observations in mice were qualitatively replicated in post-mortem hippocampal samples from two patients with AD (Braak stage 5). Together, our findings identify at the ultrastructural level distinct microglial transformations common to mouse and human in association with amyloid pathology.
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In areas with limited plaque pathology, microglial processes encircle synaptic elements more often than plaque-associated processes.
“In addition, in areas with limited plaque pathology, microglial processes encircled synaptic elements more often compared with plaque-associated processes [57].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [57]
In AD model mice, microglial cell bodies are larger and display ultrastructural signs of cellular stress, especially near plaques, and these cells are overall less phagocytic.
“Previous studies have shown that cell bodies of microglia in AD model mice were larger and displayed ultrastructural signs of cellular stress, especially those nearby plaques and that these cells were overall less phagocytic [57].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [57]
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Schlachetzki, J. C. M., & Hüll, M. (2009) · Current Alzheimer Research · doi:10.2174/156720509790147179 · Cited by 102 · cited 1× · see citing works
“The main pathological hallmarks of AD are the deposition of extracellular amyloid beta (Aβ) plaques, comprising insoluble Aβ fibrils (fAβ), and intraneuronal fibrillar tangles of tau protein [7].”
BackgroundSavage, J. C., Picard, K., Ibáñez, F. G., & Tremblay, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00803 · Cited by 93 · see citing works
Self-citationEndoplasmic Reticulum Dysfunction in Alzheimer’s Disease
Li, J., Yu, J., Jiang, T., & Tan, L. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8695-8 · Cited by 86 · cited 1× · see citing works
“It has been described in several neurodegenerative diseases, including amyotrophic lateral sclerosis and AD [63, 64].”
BackgroundHippocampal volume is an independent predictor of cognitive performance in CADASIL
O'Sullivan, M., Ngo, E., Viswanathan, A., Jouvent, E., Gschwendtner, A., Saemann, P. G., Duering, M., Pachai, C., Bousser, M.-G., Chabriat, H., et al. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.09.002 · Cited by 85 · see citing works
Chavez‐Valdez, R., Flock, D. L., Martin, L. J., & Northington, F. J. (2015) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2015.11.007 · Cited by 75 · see citing works
Malm, T., Koıstınaho, J., & Kanninen, K. M. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/517160 · Cited by 74 · cited 1× · see citing works
“To provide further insights into the implication of microglial diversity in AD, the present study aimed to define the spatial heterogeneity of microglial ultrastructure with relation to fAβ plaques, as well as neuronal dystrophy and synaptic loss, using APP-PS1Δe9 mice [38].”
MethodProperties of neuronal lipofuscin pigment in mice
Nandy, K. (1971) · Acta Neuropathologica · doi:10.1007/bf00690951 · Cited by 69 · see citing works
Remodeling of lipid bodies by docosahexaenoic acid in activated microglial cells
Tremblay, M.-E., Zhang, I., Bisht, K., Savage, J. C., Lecours, C., Parent, M., Titorenko, V., & Maysinger, D. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0580-0 · Cited by 66 · cited 11× · see citing works
“However, after ultrathin sections were made, they were collected onto polished silicon chips and treated with 2% osmium tetroxide in 1.5% potassium ferrocyanide solution, followed by 1% thiocarbohydrazide, and 1% osmium, as described in the National Center for Microscopy and Imaging Research serial blockface SEM proto…”
BackgroundMethodInfluentialSelf-citationAcharjee, S., Verbeek, M., Gómez, C., Bisht, K., Lee, B., Benoit, L., Sharkey, K. A., Benediktsson, A. M., Tremblay, M., & Pittman, Q. J. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0398-18.2018 · Cited by 63 · see citing works
Self-citationPreparation of Mouse Brain Tissue for Immunoelectron Microscopy
Tremblay, M., Riad, M., & Majewska, A. K. (2010) · Journal of Visualized Experiments · doi:10.3791/2021 · Cited by 55 · cited 1× · see citing works
“Transverse sections of the brain (50-μm-thick) were cut in PBS using a vibratome (Leica VT1000S) and kept in a cryoprotectant solution containing glycerol and ethylene glycol at − 20 °C until further processing [41, 43].”
MethodSelf-citationHexokinases link DJ-1 to the PINK1/parkin pathway
Hauser, D., Mamais, A., Conti, M., Primiani, C., Kumaran, R., Dillman, A., Langston, R., Beilina, A., Garcia, J. H., Díaz-Ruiz, A., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0212-x · Cited by 55 · see citing works
Mega, M. S., Small, G. W., Xu, M. L., Felix, J., Manese, M., Tran, N. P., Dailey, J. I., Ercoli, L. M., Bookheimer, S. Y., & Toga, A. W. (2002) · Psychosomatic Medicine · doi:10.1097/00006842-200205000-00013 · Cited by 48 · see citing works
Hui, C. W., St‐Pierre, M., Detuncq, J., Aumailley, L., Dubois, M.-J., Couture, V., Skuk, D., Marette, A., Tremblay, J. P., Lebel, M., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.06.007 · Cited by 46 · see citing works
Self-citationDifferential effect of angiotensin II and blood pressure on hippocampal inflammation in mice
Iulita, M. F., Vallerand, D., Beauvillier, M., Haupert, N., Ulysse, C. A., Gagné, A., Vernoux, N., Duchemin, S., Boily, M., Tremblay, M., et al. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1090-z · Cited by 38 · see citing works
Self-citationCorrelative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques
Bisht, K., Hajj, H. E., Savage, J. C., Sanchez, M. G., & Tremblay, M. (2016) · Journal of Visualized Experiments · doi:10.3791/54060 · Cited by 27 · cited 5× · see citing works
“Areas of interest were excised from the embedded sections, glued to resin blocks [41], and sectioned at 70–80 nm using a Leica UC7 ultramicrotome.”
MethodInfluentialSelf-citationNuntagij, P., Oddo, S., LaFerla, F. M., Kotchabhakdi, N., Ottersen, O. P., & Torp, R. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-0962 · Cited by 21 · see citing works
Esparza, T. J., Gangolli, M., Cairns, N. J., & Brody, D. L. (2018) · PLoS ONE · doi:10.1371/journal.pone.0200251 · Cited by 16 · see citing works
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Research works printed but not linked: 2
- [9]Ferreira ST Lourenco MV Oliveira MM De Felice FG Soluble amyloid-beta oligomers as synaptotoxins leading to cognitive impairment in Alzheimer’s disease Front Cell Neurosci 2015 9 9498 PMC4443025 26074767
- [62]Solé-Domènech S, Cruz DL, Capetillo-Zarate E, Maxfield FR. Ageing research reviews Ageing Research Reviews. Elsevier B.V; 2016;32:89–103. PMC5127718 27421577
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Sorted by citations
Synaptic degeneration in Alzheimer disease
Tzioras, M., McGeachan, R. I., Durrant, C. S., & Spires-Jones, T. L. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-022-00749-z · Cited by 504 · see citing works
Impact of TREM2R47H variant on tau pathology–induced gliosis and neurodegeneration
Gratuze, M., Leyns, C. E. G., Sauerbeck, A. D., St-Pierre, M.-K., Xiong, M., Kim, N., Serrano, J. R., Tremblay, M.-È., Kummer, T. T., Colonna, M., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci138179 · Cited by 252 · see citing works
“(endoplasmic reticulum dilation, condensation of the nucleo- and cytoplasm, altered mitochondria) (67, 68) and have been seen previously in pathological conditions, such as AD (69).”
BackgroundSelf-citationTherapeutic B-cell depletion reverses progression of Alzheimer’s disease
Kim, K., Wang, X., Ragonnaud, E., Bodogai, M., Illouz, T., DeLuca, M., McDevitt, R. A., Gusev, F., Okun, E., Rogaev, E., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22479-4 · Cited by 206 · see citing works
Lombardi, M., Parolisi, R., Scaroni, F., Bonfanti, E., Gualerzi, A., Gabrielli, M., de Rosbo, N. K., Uccelli, A., Giussani, P., Viani, P., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02049-1 · Cited by 188 · see citing works
“Importantly, microglia exhibited condensed, electron-dense cytoplasm and nucleoplasm, resembling “dark” microglia, a recently described phenotype of reactive cells [7] [27], characterized by pronounced chromatin remodeling, which is indicative of altered gene expression.”
BackgroundSubramanian, J., Savage, J. C., & Tremblay, M. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.592607 · Cited by 124 · see citing works
Self-citationPuntambekar, S. S., Moutinho, M., Lin, P. B.-C., Jadhav, V., Tumbleson-Brink, D., Balaji, A., Benito, M. A., Xu, G., Oblak, A., Lasagna-Reeves, C. A., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00545-9 · Cited by 113 · see citing works
“Taken as a whole, these data indicate that a) active elimination of neurons by neurodegenerative microglia may be dictated by the quality of intraneuronal pathological protein aggregates and b) microglial neurodegenerative responses modulated by CX3CR1 may be subject to region-dependent microglial heterogeneity along…”
BackgroundAPOE 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
Brain Ultrastructure: Putting the Pieces Together
Nahirney, P. C., & Tremblay, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.629503 · Cited by 111 · see citing works
Self-citationAugusto‐Oliveira, M., Arrifano, G. D. P., Delage, C. I., Tremblay, M., Lopez, M. E. C., & Verkhratsky, A. (2021) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12797 · Cited by 107 · see citing works
Self-citationMicroglia control glutamatergic synapses in the adult mouse hippocampus
Basilico, B., Ferrucci, L., Ratano, P., Golia, M. T., Grimaldi, A., Rosito, M., Ferretti, V., Reverte, I., Sanchini, C., Marrone, M. C., et al. (2021) · Glia · doi:10.1002/glia.24101 · Cited by 103 · see citing works
Self-citationTzioras, M., Daniels, M. J. D., Davies, C., Baxter, P. S., King, D., McKay, S., Varga, B. V., Popovic, K., Hernandez, M., Stevenson, A. J., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101175 · Cited by 109 · see citing works
“These data show that microglia contain synaptic protein in human brain with more ingestion in AD, more near plaques, and more in APOE4 carriers.”
InfluentialSavage, J. C., St‐Pierre, M., Carrier, M., Hajj, H. E., Novak, S. W., Sánchez, M. G., Cicchetti, F., & Tremblay, M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01782-9 · Cited by 99 · see citing works
Self-citationA neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion
Flury, A. G., Aljayousi, L., Park, H.-J., Khakpour, M., Mechler, J., Aziz, S., McGrath, J. D., Deme, P., Sandberg, C., Ibáñez, F. G., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.11.018 · Cited by 98 · see citing works
Self-citationKrukowski, K., Nolan, A., Becker, M., Picard, K., Vernoux, N., Frias, E. S., Feng, X., Tremblay, M., & Rosi, S. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.08.210 · Cited by 86 · see citing works
“In addition, in our qualitative analysis, neuronal cell bodies were distinguished by their pale nuclei and pale cytoplasm, heterochromatin pattern, as well as innervation from axon terminals (65, 68).”
BackgroundMethodInfluentialSelf-citationWalker, L. C. (2020) · Free Neuropathology · doi:10.17879/freeneuropathology-2020-3025 · Cited by 95 · see citing works
Bordeleau, M., Lacabanne, C., Fernández de Cossío, L., Vernoux, N., Savage, J. C., González-Ibáñez, F., & Tremblay, M.-È. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01914-1 · Cited by 85 · see citing works
“Dilation of the endoplasmic reticulum and/or Golgi apparatus was noted when the distance between the cisternal membranes was 50 nm or greater [56, 57].”
BackgroundSelf-citationHashemiaghdam, A., & Mroczek, M. (2020) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2020.577185 · Cited by 77 · see citing works
Microglia transcriptional states and their functional significance: Context drives diversity
Depp, C., Doman, J. L., Hingerl, M., Xia, J., & Stevens, B. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.009 · Cited by 81 · see citing works
Different phenotypes of microglia in animal models of Alzheimer disease
Wei, Y., & Li, X. (2022) · Immunity & Ageing · doi:10.1186/s12979-022-00300-0 · Cited by 71 · see citing works
Picard, K., St‐Pierre, M., Vecchiarelli, H. A., Bordeleau, M., & Tremblay, M. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104987 · Cited by 77 · see citing works
Self-citationSt‐Pierre, M., Carrier, M., Ibáñez, F. G., Šimončičová, E., Wallman, M., Vallières, L., Parent, M., & Tremblay, M. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02595-8 · Cited by 76 · see citing works
“In line with these findings, previous studies from our group identified a microglial state, the dark microglia, which are found nearby fibrillar Aβ in middle-age, 14-month-old APP-PS1 mice [mouse model of AD with a Swedish mutation in the APP and a humanized presenilin (PSEN1)] [64, 65].”
BackgroundMethodResultInfluentialSelf-citationShedding Light on the Dark Side of the Microglia
St‐Pierre, M., Šimončičová, E., Bögi, E., & Tremblay, M. (2020) · ASN NEURO · doi:10.1177/1759091420925335 · Cited by 63 · see citing works
“…observed microglia with a preserved, distinct heterochromatin pattern and a less-dark appearance that suggested the existence of an intermediate phenotype between the typical and DM (El Hajj et al., 2019), thus further supporting the idea that DM might be part of a heterogenous microglial spectrum.”
BackgroundResultInfluentialSelf-citationMicroglia gone awry: linking immunometabolism to neurodegeneration
Afridi, R., Lee, W.-H., & Suk, K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00246 · Cited by 64 · see citing works
“The dark microglia are named after their dark appearance under an electronmicroscope (Bisht et al., 2016; El Hajj et al., 2019).”
BackgroundThe role of the immune system in driving neuroinflammation
Ní Chasaide, C., & Lynch, M. A. (2020) · Brain and Neuroscience Advances · doi:10.1177/2398212819901082 · Cited by 72 · see citing works
“Evidence suggests that these cells are hypermotile (Gyoneva et al., 2016) and less phagocytic, although they contain fibrillar material (El Hajj et al., 2019), so they can phagocytose, but not process, amyloid-β (Aβ).”
BackgroundMicroglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration
Woollacott, I., Toomey, C. E., Strand, C., Courtney, R. J., Benson, B. C., Rohrer, J. D., & Lashley, T. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01907-0 · Cited by 61 · see citing works
Bollinger, J. L., Dadosky, D. T., Flurer, J. K., Rainer, I. L., Woodburn, S. C., & Wohleb, E. S. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01519-7 · Cited by 53 · see citing works
Microglial Ultrastructure in the Hippocampus of a Lipopolysaccharide-Induced Sickness Mouse Model
Savage, J. C., St‐Pierre, M., Hui, C. W., & Tremblay, M. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01340 · Cited by 51 · see citing works
Self-citationBordeleau, M., Comin, C. H., de Cossío, L. F., Lacabanne, C., Freitas-Andrade, M., Ibáñez, F. G., Raman-Nair, J., Wakem, M., Chakravarty, M., Costa, L. D. F., et al. (2022) · Communications Biology · doi:10.1038/s42003-021-02947-9 · Cited by 51 · see citing works
Self-citationDysregulated CD200-CD200R signaling in early diabetes modulates microglia-mediated retinopathy
Pfeifer, C. W., Walsh, J. T., Santeford, A. C., Lin, J. B., Beatty, W. L., Terao, R., Liu, Y. A., Hase, K., Ruzycki, P. A., & Apte, R. S. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2308214120 · Cited by 48 · see citing works
Sharma, M., Pal, P., & Gupta, S. K. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105761 · Cited by 48 · see citing works
McFarland, K. N., & Chakrabarty, P. (2022) · Neurotherapeutics · doi:10.1007/s13311-021-01179-3 · Cited by 48 · see citing works
Bordeleau, M., de Cossío, L. F., Lacabanne, C., Savage, J. C., Vernoux, N., Chakravarty, M. M., & Tremblay, M. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100281 · Cited by 46 · see citing works
Self-citationTargeting innate immunity to protect and cure Alzheimer’s disease: opportunities and pitfalls
Cisbani, G., & Rivest, S. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01083-4 · Cited by 43 · see citing works
“Of note, brains of subjects with AD showed an intensified immune response in both post-mortem studies [33] as well as in vivo [34] and microglia displayed ultrastructural modifications when associated with Aβ [35].”
BackgroundSelf-citationAloi, M. S., Prater, K. E., Sánchez, R. E. A., Beck, A., Pathan, J. L., Davidson, S., Wilson, A., Keene, C. D., de la Iglesia, H., Jayadev, S., et al. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02745-6 · Cited by 43 · see citing works
“In addition, in areas with limited plaque pathology, microglial processes encircled synaptic elements more often compared with plaque-associated processes [57].”
BackgroundResultDe Felice, E., Gonçalves de Andrade, E., Golia, M. T., González Ibáñez, F., Khakpour, M., Di Castro, M. A., Garofalo, S., Di Pietro, E., Benatti, C., Brunello, N., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02655-z · Cited by 39 · see citing works
Self-citationde Andrade, E. G., Šimončičová, E., Carrier, M., Vecchiarelli, H. A., Robert, M.-È., & Tremblay, M. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.647378 · Cited by 37 · see citing works
Self-citationLiang, F., Huang, T., Li, B., Zhao, Y., Zhang, X., & Xu, B. (2020) · Neuroreport · doi:10.1097/wnr.0000000000001429 · Cited by 38 · see citing works
McKee, C., Hoffos, M., Vecchiarelli, H. A., & Tremblay, M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1125982 · Cited by 38 · see citing works
Self-citationLecours, C., St‐Pierre, M., Picard, K., Bordeleau, M., Bourque, M., Awogbindin, I. O., Benadjal, A., Ibáñez, F. G., Gagnon, D., Cantin, L., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.07.044 · Cited by 33 · see citing works
Self-citationIkzf1 as a novel regulator of microglial homeostasis in inflammation and neurodegeneration
Ballasch, I., García-García, E., Vila, C., Pérez-González, A., Sancho‐Balsells, A., Fernández, J., Soto, D., Puigdellívol, M., Gasull, X., Alberch, J., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.01.016 · Cited by 35 · see citing works
Digestive exophagy: Phagocyte digestion of objects too large for phagocytosis
Maxfield, F. R., Barbosa-Lorenzi, V. C., & Singh, R. K. (2019) · Traffic · doi:10.1111/tra.12712 · Cited by 33 · see citing works
Enlow, W., Bordeleau, M., Piret, J., Ibáñez, F. G., Uyar, O., Venable, M.-C., Goyette, N., Carbonneau, J., Tremblay, M., & Boivin, G. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02221-z · Cited by 30 · see citing works
“It is suggested that microglia break down dead or dying neurons into pieces using exophagy before their phagocytic engulfment and digestion [46], hence allowing them to digest large debris and cells [49, 50].”
BackgroundSelf-citationVecchiarelli, H. A., & Tremblay, M. (2023) · Annual Review of Genetics · doi:10.1146/annurev-genet-022223-093643 · Cited by 29 · see citing works
Self-citationGonzález Ibáñez, F., Halvorson, T., Sharma, K., McKee, C. G., Carrier, M., Picard, K., Vernoux, N., Bisht, K., Deslauriers, J., Lalowski, M., et al. (2023) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2023.09.006 · Cited by 28 · see citing works
Self-citationSt-Pierre, M.-K., Carrier, M., Lau, V., & Tremblay, M.-È. (2022) · Methods in Molecular Biology · doi:10.1007/978-1-0716-2409-8_3 · Cited by 29 · see citing works
Self-citationImaging the Neuroimmune Dynamics Across Space and Time
Carrier, M., Robert, M.-È., Ibáñez, F. G., Desjardins, M., & Tremblay, M. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00903 · Cited by 27 · see citing works
Self-citationHypothalamic Microglial Heterogeneity and Signature under High Fat Diet–Induced Inflammation
Mendes, N. F., Jara, C. P., Zanesco, A. M., & ARAUJO, E. P. D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052256 · Cited by 26 · see citing works
St-Pierre, M.-K., VanderZwaag, J., Loewen, S., & Tremblay, M. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.932572 · Cited by 25 · see citing works
Self-citationSt‐Pierre, M., Carrier, M., Ibáñez, F. G., Khakpour, M., Wallman, M., Parent, M., & Tremblay, M. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02752-7 · Cited by 26 · see citing works
Self-citationKim, Y. S., Choi, S., Kim, K.-Y., Pelaez, J. M. N., Perkins, G. A., Choi, S., Kim, J., Nazarenkov, N., Rissman, R. A., Ju, W., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03214-4 · Cited by 23 · see citing works
“Dilated ER has been reported in several neurodegenerative diseases, including amyotrophic lateral sclerosis and AD [37].”
Microglia in Alzheimer’s Disease
Süß, P., & Schlachetzki, J. C. M. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200212155234 · Cited by 26 · see citing works
St‐Pierre, M., Ibáñez, F. G., Kroner, A., & Tremblay, M. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02953-0 · Cited by 22 · see citing works
Self-citationStoiljković, M., Gutierrez, K. O., Kelley, C., Horváth, T. L., & Hajós, M. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210041 · Cited by 21 · see citing works
“…progression microglia in response to oligomeric and plaque A (cid:2) challenge tend to undergo substantial ultrastructural changes leading to aberrant activation involved in A (cid:2) -mediated neuronal dysfunctions and pathologic loss of synapses in cognitive-related brain regions [55, 56].”
Abo-Zaid, O. A., Sallam, M. W., & Ahmed, E. S. A. (2022) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2022.26 · Cited by 24 · see citing works
“These plaques caused neuronal dystrophy, and finally neuronal death (34) that is represented by the increased number of dark neurons in the AD group.”
BackgroundBrain structure and structural basis of neurodegenerative diseases
Yang, J., Sui, S., & Liu, Z. (2022) · Biophysics Reports · doi:10.52601/bpr.2022.220013 · Cited by 20 · see citing works
Fundamental Neurochemistry Review: Lipids across microglial states
Traetta, M. E., Vecchiarelli, H. A., & Tremblay, M. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16259 · Cited by 19 · see citing works
Self-citationMultiscale ATUM-FIB Microscopy Enables Targeted Ultrastructural Analysis at Isotropic Resolution
Kislinger, G., Gnaegi, H., Kerschensteiner, M., Simons, M., Misgeld, T., & Schifferer, M. (2020) · iScience · doi:10.1016/j.isci.2020.101290 · Cited by 20 · see citing works
Vignon, A., Dudon, G., Oliva, G., Thirard, S., Alenda, U. G., Brugoux, A., Cazevieille, C., Imbert, J., Bellières, C., Lehmann, S., et al. (2025) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2025.138640 · Cited by 19 · see citing works
The Dual Nature of Microglia in Alzheimer’s Disease: A Microglia-Neuron Crosstalk Perspective
Xie, Z., Meng, J., Wu, Z., Nakanishi, H., Hayashi, Y., Kong, W., Lan, F., Narengaowa, Yang, Q., Qing, H., et al. (2022) · The Neuroscientist · doi:10.1177/10738584211070273 · Cited by 20 · see citing works
Using focused ultrasound to modulate microglial structure and function
Grewal, S., de Andrade, E. G., Kofoed, R. H., Matthews, P. M., Aubert, I., Tremblay, M.-È., & Morse, S. V. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1290628 · Cited by 24 · see citing works
Self-citationBobotis, B. C., Halvorson, T., Carrier, M., & Tremblay, M. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1317125 · Cited by 21 · see citing works
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“neuron-microglia interaction remains unknown [17].”
BackgroundPhenomic Microglia Diversity as a Druggable Target in the Hippocampus in Neurodegenerative Diseases
Lana, D., Magni, G., Landucci, E., Wenk, G. L., Pellegrini-Giampietro, D. E., & Giovannini, M. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813668 · Cited by 19 · see citing works
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Self-citationMicroglial Reactivity Correlates with Presynaptic Loss Independent of β‐Amyloid and Tau
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“One postmortem study 49 demonstrated that microglial processes contained synaptic elements in the hippocampus of AD patients, and the amyloidosis mice experienced greater synaptic engulfment by microglia compared to wild-type mice.”
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“Additionally, other microglial subsets that emerge during disease progression have been observed, which differ from the originally described DAMs, including plaques associated microglia and dark microglia (Hashemiaghdam and Mroczek, 2020; Bisht et al., 2016; El Hajj et al., 2019).”
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“Many authors consider that microglial cells accumulate in areas more strongly associated with amyloid deposits, even infiltrating amyloid plaques, although they also appear in less severely affected areas.(198,199) In”
BackgroundPromising molecular targets for pharmacological therapy of neurodegenerative pathologies
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The Role of Glia in Addiction: Dopamine as a Modulator of Glial Responses in Addiction
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Self-citationUltrastructural features of psychological stress resilience in the brain: a microglial perspective
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Self-citationMicroglia heterogeneity during neuroinflammation and neurodegeneration in the mouse retina
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“This is in agreement with previous studies in the CNS (Bisht K et al. 2016; El Hajj H et al. 2019).”
InfluentialCell type specific isolation of primary astrocytes and microglia from adult mouse spinal cord
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Iovino, L., VanderZwaag, J., Kaur, G., Khakpour, M., Giusti, V., Donadon, M., Chiavegato, A., Lopes, L. T., Greggio, E., Tremblay, M., et al. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106481 · Cited by 7 · see citing works
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Self-citationMicroglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States
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“…neurons from Aβ oligomers that contribute to synapse disruption and cognitive deficits [169, 170], as a consequence of their interaction with Aβ and Aβ plaques, microglia display impaired surveillance activity and dampened homeostatic functions [171] and promote the spread of Aβ in the brain [172].”
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Self-citationEvolving insights into the identity and function of dark microglia
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“Indeed, a study that examined the ultrastructure of organelles within the main body and processes of microglia, noted that there were more non-empty inclusions within phagocytic vesicles of processes versus the main body 103 .”
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How Many Alzheimer–Perusini’s Atypical Forms Do We Still Have to Discover?
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Biphasic Role of Microglia in Healthy and Diseased Brain
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Caveolin-1 Regulates Ultrastructural Alterations of Astrocytes in Chronic Cerebral Hypoperfusion
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- Authors
- El Hajj, H., Savage, J. C., Bisht, K., Parent, M., Vallières, L., Rivest, S., & Tremblay, M.-È.
- Affiliations
- Centre de recherche du CHU de Québec-Université Laval (CA)
- Université Laval (CA)
- Corresponding author
- Tremblay, Marie-Ève
- Venue
- Journal of Neuroinflammation
- Published
- 2019-04-16
- Volume
- 16
- Issue
- 1
- Pages
- 87-87
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC6469225
- OpenAlex
- W2946033659
- Cited by
- 119
- References
- 95
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 23 · 2023: 16 · 2022: 22 · 2021: 18 · 2020: 18 · 2019: 4
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Fonds de recherche en santé du Québec
- Lebanese Ministry of Education and Higher Education
- Fondation du CHU de Québec
- The Banting Research Foundation
- The Scottish Rite Charitable Foundation of Canada
- NEURON-ERANET
- 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, microglial heterogeneity, amyloid plaques, amyloid fibrils, APPswe/PS1ΔE9 mice, hippocampal CA1, microglial phagocytosis, neuronal dystrophy, Braak stages, neuroinflammation
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Hippocampus, Humans, Amyloid beta-Peptides, Microglia, Mice
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