The DOI matches its Crossref record; 69 of the 70 references it cites were found in a registry or an index.
Inflammatory Response in the Hippocampus of PS1M146L/APP751SLMouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic
Open accessAbstract
Although the microglial activation is concomitant to the Alzheimer's disease, its precise role (neuroprotection vs neurodegeneration) has not yet been resolved. Here, we show the existence of an age-dependent phenotypic change of microglial activation in the hippocampus of PS1xAPP model, from an alternative activation state with Aβ phagocytic capabilities (at 6 months) to a classic cytotoxic phenotype (expressing TNF-α and related factors) at 18 months of age. This switch was coincident with high levels of soluble Aβ oligomers and a significant pyramidal neurodegeneration.In vitro assays, using astromicroglial cultures, demonstrated that oligomeric Aβ42 and soluble extracts from 18-month-old PS1xAPP hippocampus produced a potent TNF-α induction whereas monomeric Aβ42 and soluble extract from 6- or 18-month-old control and 6-month-old PS1xAPP hippocampi produced no stimulation. This stimulatory effect was avoided by immunodepletion using 6E10 or A11. In conclusion, our results show evidence of a switch in the activated microglia phenotype from alternative, at the beginning of Aβ pathology, to a classical at advanced stage of the disease in this model. This change was induced, at least in part, by the age-dependent accumulation of extracellular soluble Aβ oligomers. Finally, these cytotoxic activated microglial cells could participate in the neuronal lost observed in AD.
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“Within the AD brain, there is a chronic activation of microglia associated with inflammatory cytokines including TNF␣ that can substantially block of ability of the microglia to remove 47,49,50 or degrade A. 51,52”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [49]
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“several studies have suggested that microglial activation plays a beneficial role in early stages of AD pathology, but contributes to disease worsening in late stages of AD [66–68].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [66]
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1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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“The observed 6E10-positive bands corresponded with the reported Mr for the oligomeric A forms, detected by Western blots (see Lambert et al., 2007), and also similar to soluble oligomers identified in other aged tg models (Lesné et al., 2006).”
BackgroundRetractedAmyloid 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
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Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., & Glabe, C. G. (2003) · Science · doi:10.1126/science.1079469 · Cited by 4,064 · cited 1×
“The soluble fractions (S1) were obtained by ultracentrifugation of the homogenates as described previously (Kayed et al., 2003).”
MethodWest, M. J., Slomianka, L., & Gundersen, H. J. G. (1991) · The Anatomical Record · doi:10.1002/ar.1092310411 · Cited by 2,994 · cited 2×
“The software calculated the estimated total number of cresyl-violet stained nuclei in the CA1 region using the optical fractionator formula (West et al., 1991; Schmitz and Hof, 2005), N 1/bsf.1/ssf.1/asf.1/hsf.”
MethodIL-17 family cytokines and the expanding diversity of effector T cell lineages
Weaver, C. T., Hatton, R. D., Mangan, P. R., & Harrington, L. E. (2007) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141557 · Cited by 1,842 · cited 1×
“The recruitment of CD4 Th1-cells in experimental autoimmune encephalomyelitis (EAE; a disease similar to human multiple sclerosis) induced the production of, among other cytotoxic factors, TNF- (Dhib-Jalbut et al., 2006; Weaver et al., 2007).”
BackgroundControl 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 · cited 1×
“…reported that aging and/or A could decrease the neuronal expression of microglial inhibitory factors, such as CD200, fractalkine or neurotransmitters (Acetylcholine or noradrenaline) (Cardona et al., 2006; Chitnis et al., 2007; Heneka and O’Banion, 2007; Lyons et al., 2007a; Duan et al., 2008).”
BackgroundThe efficiency of systematic sampling in stereology—reconsidered
GUNDERSEN, H. J. G., JENSEN, E. B. V., KIÊU, K., & NIELSEN, J. (1999) · Journal of Microscopy · doi:10.1046/j.1365-2818.1999.00457.x · Cited by 1,317 · cited 1×
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MethodWyss-Coray (2006) · doi:10.1038/nm1484 · Cited by 1,284 · cited 1×
“As proposed by the inflammation hypothesis of Alzheimer’s disease (AD), the neurodegenerative process could be exacerbated by a chronic inflammatory response to -amyloid (A ) peptides (for review, see Griffin et al., 1998; Wyss-Coray, 2006; Heneka and O’Banion, 2007).”
BackgroundSimard, A. R., Soulet, D., Gowing, G., Julien, J.-P., & Rivest, S. (2006) · Neuron · doi:10.1016/j.neuron.2006.01.022 · Cited by 1,265 · cited 2×
“We observed a close spatial and temporal parallelism between A deposits and microglial activation (Simard et al., 2006).”
Background
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Items 101–200 of 383
Menopause, obesity and inflammation: interactive risk factors for Alzheimer’s disease
Christensen, A., & Pike, C. J. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00130 · Cited by 112
“Similarly, microglia in an AD mouse model mice were shown to be anti-inflammatory early in the disease, but to be activated later after the pathology had progressed (Jimenez et al., 2008).”
BackgroundMicroglial activation in early Alzheimer trajectory is associated with higher gray matter volume
Femminella, G. D., Dani, M., Wood, M., Fan, Z., Calsolaro, V., Atkinson, R., Edginton, T. L., Hinz, R., Brooks, D. J., & Edison, P. (2019) · Neurology · doi:10.1212/wnl.0000000000007133 · Cited by 109
Microglia Polarization in Alzheimer’s Disease: Mechanisms and a Potential Therapeutic Target
Wang, Q., Yao, H., Liu, W., Ya, B., Cheng, H., Xing, Z., & Wu, Y. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.772717 · Cited by 111
“Moreover, it was indicated that M2 microglia switched into the M1 phenotype at the advanced stage of AD (Jimenez et al., 2008).”
BackgroundThe Essential Role of Soluble Aβ Oligomers in Alzheimer’s Disease
Wang, Z.-X., Tan, L., Liu, J., & Yu, J.-T. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9143-0 · Cited by 110
“Upon interaction with PRR, Aβ oligomers can activate microglia [120].”
BackgroundReed-Geaghan, E. G., Reed, Q. W., Cramer, P. E., & Landreth, G. E. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2637-10.2010 · Cited by 106
“, 2006) or the reverse (Jimenez et al., 2008) is controversial, and resolution of this problem is hampered by the inability to perform phenotypic analysis at the cellular level.”
BackgroundMicroglial Activation in Alzheimers Disease
Schlachetzki, J. C. M., & Hüll, M. (2009) · Current Alzheimer Research · doi:10.2174/156720509790147179 · Cited by 105
Torres, M., Jiménez, S., Sanchez-Varo, R. M., Navarro, V., Trujillo‐Estrada, L., Sánchez‐Mejías, E., Carmona, I., Dávila, J. C., Vizuete, M., Gutiérrez, A., et al. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-59 · Cited by 103
Self-citationInflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings
de Oliveira, J., Kucharska, E., Garcez, M. L., Rodrigues, M. S., Quevedo, J., Moreno‐González, I., & Budni, J. (2021) · Cells · doi:10.3390/cells10102581 · Cited by 110
“It is well known that Aβ causes neuroinflammation, and many studies have demonstrated the role of inflammation in the early stages of AD development [36,37].”
BackgroundHigher Serum sTNFR1 Level Predicts Conversion from Mild Cognitive Impairment to Alzheimer's Disease
Diniz, B. S., Teixeira, A. L., Ojopi, E. P. B., Talib, L. L., Mendonça, V. A., Gattaz, W. F., & Forlenza, O. V. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100921 · Cited by 99
“In cellular and animal models of AD, the amyloid-β peptide (Aβ) potently stimulates TNF-α expression [13,14].”
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“12,29,36 In this study, we used a fluid percussion device to induce axonal injury in mice.”
Glial connexin expression and function in the context of Alzheimer's disease
Koulakoff, A., Mei, X., Orellana, J. A., Sáez, J. C., & Giaume, C. (2011) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2011.10.001 · Cited by 100
“No change Cx43[22, 26] GJC [100] A β -treated microglia Cx43[22] HCA[22] A β that microglial responses are multifaceted, with differences during the progression of the disease and between sub-populations of microglial cells, as well as on their relation with A β plaques [71, 72].”
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“The downstream pathological events of Aβ deposits such as inflammation have been studied by using APPSL/ PS1M146L mutant mice as an experimental model (Jimenez et al. 2008).”
Baglietto-Vargas, D., Moreno-Gonzalez, I., Sanchez-Varo, R., Jimenez, S., Trujillo-Estrada, L., Sanchez-Mejias, E., Torres, M., Romero-Acebal, M., Ruano, D., Vizuete, M., et al. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-100066 · Cited by 98
“In this sense, we have described an association between extracellular Aβ and/or cytotoxic glial environment and the neurodegeneration of hippocampal principal cells [23] in layer V pyramidal cells of the entorhinal cortex in this PS1/AβPP”
BackgroundMethodInfluentialSelf-citationRodríguez, J. J., Witton, J., Olabarria, M., Noristani, H. N., & Verkhratsky, A. (2010) · Cell Death & Disease · doi:10.1038/cddis.2009.2 · Cited by 114
Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice
Babcock, A. A., Ilkjær, L., Clausen, B. H., Villadsen, B., Dissing-Olesen, L., Bendixen, A. T. M., Lyck, L., Lambertsen, K. L., & Finsen, B. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.03.006 · Cited by 107
Inflammation in transgenic mouse models of neurodegenerative disorders
Schwab, C., Klegeris, A., & McGeer, P. L. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.10.013 · Cited by 97
“Jimenez and colleagues [69] reported that in 6-month-old APP/PS1 mice, microglia are TNF-α negative and phagocytose Aβ in accordance with an anti-inflammatory phenotype, while microglia of 18-month-old mice have switched to a proinflammatory phenotype with increased TNF-α and inducible nitric oxide synthase (iNOS) exp…”
BackgroundDiverse activation of microglia by chemokine (C-C motif) ligand 2 overexpression in brain
Selenica, M. B., Alvarez, J. A., Nash, K. R., Lee, D. C., Cao, C., Lin, X., Reid, P., Mouton, P. R., Morgan, D., & Gordon, M. N. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-86 · Cited by 99
Larouche, E., Hudon, C., & Goulet, S. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.05.058 · Cited by 93
Amyloid‐β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease
Sanchez‐Mico, M. V., Jimenez, S., Gomez‐Arboledas, A., Muñoz‐Castro, C., Romero‐Molina, C., Navarro, V., Sanchez‐Mejias, E., Nuñez‐Diaz, C., Sanchez‐Varo, R., Galea, E., et al. (2021) · Glia · doi:10.1002/glia.23943 · Cited by 93
“As reported previously, the soluble S1 fractions, isolated from APP mice brain, contained Abeta oligomeric forms (see Jimenez et al., 2008; Kayed et al., 2003, 2007; Moreno-Gonzalez et al., 2009; Torres et al., 2012; Yang, Li, Xu, Walsh, & Selkoe, 2017).”
BackgroundMethodInfluentialSelf-citationLong-Term Dabigatran Treatment Delays Alzheimer’s Disease Pathogenesis in the TgCRND8 Mouse Model
Cortés‐Canteli, M., Kruyer, A., Fernandez‐Nueda, I., Marcos-Díaz, A., Cerón, C., Richards, A. T., Jno-Charles, O. C., Rodríguez, I., Callejas, S., Norris, E. H., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.07.081 · Cited by 95
“Neuroinflammation in AD is also characterized by infiltration of peripheral T cells into the brain (35).”
CD45 Deficiency Drives Amyloid-β Peptide Oligomers and Neuronal Loss in Alzheimer's Disease Mice
Zhu, Y., Hou, H., Rezai-Zadeh, K. P., Giunta, B. N., Ruscin, A., Gemma, C., Jin, J., Dragicevic, N., Bradshaw, P. C., Rasool, S., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3268-10.2011 · Cited by 90
Neurotoxicity by microglia: Mechanisms and potential therapeutic strategy
Takeuchi, H. (2010) · Clinical and Experimental Neuroimmunology · doi:10.1111/j.1759-1961.2009.00001.x · Cited by 88
Impact of age-related neuroglial cell responses on hippocampal deterioration
Ojo, J. O., Rezaie, P., Gabbott, P. L. A., & Stewart, M. G. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00057 · Cited by 83
“…consequences and functional deficits can be rescued by antiinflammatory agents such as IL-4, CD200, IL-10, minocycline and eicosapentaenoic acid (EPA), which are inhibitors of glial activation (Lynch, 1998b; Kelly et al., 2003; Lyons et al., 2007a,b; Minogue et al., 2007; Clarke et al., 2008).”
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Salvadores, N., Moreno‐González, I., Gamez, N., Quiroz, G., Vegas‐Gomez, L., Escandón, M., Jiménez, S., Vitórica, J., Gutiérrez, A., Soto, C. A., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01332-9 · Cited by 87
“Dot blot Dot blots were done as described previously [48].”
MethodLoeffler, D. A. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-230025 · Cited by 90
Xie, L., Zhang, N., Zhang, Q., Li, C., Sandhu, A. F., III, G. W., Lin, S., Lv, P., Liu, Y., Wu, Q., et al. (2020) · Aging · doi:10.18632/aging.103663 · Cited by 48
“In a previous study, Aβ plaques surrounded by M2 microglia were observed in 6-month-old PS1/APP mice, but more abundant plaques were observed in 18-month-old mice when M2 microglia began to convert to the M1 phenotype [29].”
BackgroundGlia-Driven Neuroinflammation and Systemic Inflammation in Alzheimer’s Disease
Hashioka, S., Wu, Z., & Klegeris, A. (2021) · Current Neuropharmacology · doi:10.2174/1570159x18666201111104509 · Cited by 78
“As discussed above, microglia recognize Aβ, but depending on its aggregation state, functional consequences of this interaction could be very different; thus, the oligomeric Aβ is a stronger inducer of M1 phenotype than the fibrillar form of Aβ [74], while microglia surrounding amyloid plaques generally manifest M2 ph…”
BackgroundZuo, Z., Qi, F., Yang, J., Wang, X., Wu, Y., Wen, Y., Yuan, Q., Zou, J., Guo, K., & Yao, Z. B. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.02.001 · Cited by 78
Sánchez‐Mejías, E., Nuñez‐Diaz, C., Sanchez-Varo, R. M., Gómez-Arboledas, Á., García‐León, J. A., Fernandez-Valenzuela, J. J., Mejias‐Ortega, M., Trujillo‐Estrada, L., Baglietto‐Vargas, D., Moreno‐González, I., et al. (2019) · Brain Pathology · doi:10.1111/bpa.12785 · Cited by 79
“Immunopositive cells in mice and human brain sections were stereologically quantified as previously reported (5, 39, 55, 63, 71, 82) using an Olympus BX61 microscope interfaced with a computer and an Olympus DP71 digital camera, and the NewCAST (Computer Assisted Stereological Toolbox) software package (Olympus, Denma…”
MethodSelf-citationIslet amyloid polypeptide: Another key molecule in Alzheimer’s pathogenesis?
Zhang, Y., & Song, W. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.001 · Cited by 79
“, 2007), microglia and astrocyte activation (Hu et al., 1998; Jimenez et al., 2008; Tomiyama et al., 2010), and neuronal loss (Kayed et al.”
BackgroundRivera-Escalera, F., Pinney, J. J., Owlett, L., Ahmed, H., Thakar, J., Olschowka, J. A., Elliott, M. R., & O’Banion, M. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1645-7 · Cited by 75
Efficacy and mechanism of cGAMP to suppress Alzheimer’s disease by elevating TREM2
Xu, Q., Xu, W., Cheng, H., Yuan, H., & Tan, X. (2019) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2019.07.004 · Cited by 75
Das, R. C., Rauf, A., Akhter, S., Islam, M. N., Emran, T. B., Mitra, S., Khan, I. N., & Mubarak, M. S. (2021) · Molecules · doi:10.3390/molecules26123696 · Cited by 79
“In this context, participation of CD14, CD36, and Toll-like receptors in Aβinduced microglia activation clearly demonstrates that innate immunity is associated with AD pathogenesis [80,81].”
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“Controversial findings from Jimenez et al. (2008) argue that as AD pathology progresses there is a switch from M2 toward an M1 state.”
BackgroundComplement System in Alzheimer’s Disease
Shah, A., Kishore, U., & Shastri, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413647 · Cited by 76
“Anti-inflammatory cytokines such as IL-4, IL-9, IL-10, IL-11, and transforming growth factor (TGF)-β1 are also produced during neuroinflammatory events to potentially maintain a homeostatic balance to prevent excessive neuroinflammation [16,35,36].”
BackgroundInnate Immunity in Alzheimer’s Disease: A Complex Affair
Guillot‐Sestier, M., & Town, T. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527311312050008 · Cited by 72
“Another explanation involves the particular phenotype that microglia adopt during the course of the disease, which fails to avail these cells of the appropriate molecular tools for amyloid clearance [82].”
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Multiple inflammatory profiles of microglia and altered neuroimages in APP/PS1 transgenic AD mice
Liu, L., Liu, Y., Li, N., Huang, R., Zheng, X., Huang, L., Hou, S.-X., & Yuan, Q. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.01.003 · Cited by 71
Targeting Microglia in Alzheimer’s Disease: Pathogenesis and Potential Therapeutic Strategies
Sun, Z., Zhang, X., So, K.-F., Jiang, W., & Chiu, K. (2024) · Biomolecules · doi:10.3390/biom14070833 · Cited by 71
“Additionally, they may adopt alternative reactive states to counteract Aβ-induced cytotoxicity toward neighboring neurons or synapses [16] and create a physical barrier that inhibits plaque spread [17].”
BackgroundTNFα induces survival through the FLIP-L-dependent activation of the MAPK/ERK pathway
Marqués-Fernàndez, F., Planells‐Ferrer, L., Gozzelino, R., Galenkamp, K. M. O., Reix, S., Llecha-Cano, N., López‐Soriano, J., Yuste, V. J., Moubarak, R. S., & Comella, J. X. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.25 · Cited by 70
Sanberg, P. R., Eve, D. J., Willing, A. E., Garbuzova-Davis, S. N., Tan, J., Sanberg, C. D., Allickson, J. G., Cruz, L. E. G., & Borlongan, C. V. (2010) · Cell Transplantation · doi:10.3727/096368910x532855 · Cited by 72
A Novel Blood Test for the Early Detection of Alzheimer's Disease
Rye, P. D., Booij, B. B., Grave, G., Lindahl, T., Kristiansen, L., Andersen, H., Horndalsveen, P. O., Nygaard, H. A., Naik, M., Hoprekstad, D., et al. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101521 · Cited by 69
Neuroinflammation in Alzheimer's disease: an understanding of physiology and pathology
Obulesu, M., & Jhansilakshmi, M. (2013) · International Journal of Neuroscience · doi:10.3109/00207454.2013.831852 · Cited by 66
“These findings were reproduced in some AD mouse models, such as the APP/PS1 mouse, which demonstrated that there was a distinctive shift from M2 to M1 microglial activation in the hippocampus of aged rodents [55].”
ResultInvolvement of cysteinyl leukotriene receptor 1 in Aβ1–42-induced neurotoxicity in vitro and in vivo
Tang, S., Hong, H., Chen, L., Mei, Z.-L., Ji, M., Xiang, G., Li, N., & Ji, H. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.036 · Cited by 67
“It has been shown that inflammatory cytokines, chemokines, proteases, and reactive oxygen species can augment Ab formation (Daniela et al., 2010; Giunta et al., 2008; Guo et al., 2002; Jimenez et al., 2008).”
BackgroundYe, X., Feng, T., Tammineni, P., Chang, Q., Jeong, Y. Y., Margolis, D. J., Cai, H., Kusnecov, A. W., & Cai, Q. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2851-16.2017 · Cited by 62
“…A11 antibody that detects intracellular A oligomers, a soluble amyloid conformation, but not APP and its cleaved products C99 (Kayed et al., 2003; Jimenez et al., 2008, 2011; Zempel et al., 2010), we further showed that elevated Snapin expression reduces intracellular A accumulation in the…”
BackgroundNeuroinflammation and Copper in Alzheimer’s Disease
Choo, X. Y., Alukaidey, L., White, A. R., & Grubman, A. (2013) · International Journal of Alzheimer s Disease · doi:10.1155/2013/145345 · Cited by 70
“In an in vivo study involving the APP/PS1 AD mouse model, an age-dependent switch of microglial activation state, from M2 to M1, was observed [71].”
BackgroundMicroglial KCa3.1 Channels as a Potential Therapeutic Target for Alzheimer’s Disease
Maezawa, I., Jenkins, D. P., Jin, B. E., & Wulff, H. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/868972 · Cited by 64
“Microglia, the resident macrophages and major mediator of neuroinflammation in the brain, can be activated by a variety of pathologic stimuli including the amyloid aggregates formed by amyloidβ protein (Aβ) [15–17].”
BackgroundImmunomodulatory role of mesenchymal stem cells in Alzheimer's disease
Zhang, L., Dong, Z., & Zhang, J. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117405 · Cited by 63
Targeting Microglia-Synapse Interactions in Alzheimer’s Disease
Piccioni, G., Mango, D., Saidi, A., Corbo, M., & Nisticò, R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052342 · Cited by 64
“Microglia clustering plaques for phagocytosis of Aβ has characterized by M2 activation phenotype [62].”
BackgroundŁabuzek, K., Liber, S., Gabryel, B., & Okopień, B. (2010) · Pharmacological Reports · doi:10.1016/s1734-1140(10)70343-1 · Cited by 64
Pintado, C., Gavilán, M. P., Gavilán, E., García-Cuervo, L., Gutiérrez, A., Vitórica, J., Castaño, A., Rios, R. M., & Ruano, D. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-87 · Cited by 63
“Although acute neuroinflammation plays a protective role [6-8], chronic neuroinflammation is frequently considered detrimental and damaging to nervous tissue [2,3].”
BackgroundSelf-citationTowards PET imaging of the dynamic phenotypes of microglia
Beaino, W., Janssen, B., Vugts, D. J., de Vries, H. E., & Windhorst, A. D. (2021) · Clinical & Experimental Immunology · doi:10.1111/cei.13649 · Cited by 63
“advanced stage of disease in this model, which is induced in part by the age- dependent accumulation of soluble Aβ oligomers [30].”
BackgroundInfluentialWang, M., Tang, G., Zhou, C., Guo, H., Hu, Z., Hu, Q., & Li, G. (2023) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2023.110387 · Cited by 62
APP transgenic mice for modelling behavioural and psychological symptoms of dementia (BPSD)
Lalonde, R., Fukuchi, K., & Strazielle, C. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.02.011 · Cited by 66
“The APP751SWE/LD +PS1/M146L mice have Aβ plaques as early as 2.5 months of age and age-related microglial activation, first with the appearance of a phagocytic followed by a cytotoxic phenotype (Jimenez et al., 2008), and pyramidal cell loss in hippocampus (Schmitz et al., 2004).”
BackgroundInfluentialFernandez-Valenzuela, J. J., Sanchez-Varo, R. M., Muñoz‐Castro, C., Castro, V. D., Sánchez‐Mejías, E., Navarro, V., Jiménez, S., Nuñez‐Diaz, C., Gómez-Arboledas, Á., Moreno‐González, I., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-71767-4 · Cited by 63
Self-citationXu, Y., Au, N. P. B., & Ma, C. H. E. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.896852 · Cited by 68
“However, as disease progressed, the increased levels of neurotoxic pro-inflammatory cytokines switched the microglial phenotype from M2 to M1 phenotype with impaired microglial phagocytosis of Aβ plaques (Jimenez et al., 2008).”
BackgroundInflammation and Microglia Actions in Alzheimer’s Disease
Combs, C. K. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9165-3 · Cited by 62
“This increase in TNFα-positive, YM-1-negative microglia with age corresponded to an increase in IL-4-immunoreactive, Th2type CD3 + Tcells in the aged animals ( Jimenez et al. 2008 ).”
BackgroundMethodInfluentialMitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis
Scheffler, K., Krohn, M., Dunkelmann, T., Stenzel, J., Miroux, B., Ibrahim, S. M., Halbach, O. V. B. U., Heinze, H., Walker, L. C., Gsponer, J. A., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-0980-x · Cited by 61
“Senescence leads to the accumulation of random mitochondrial changes in cells and tissues and to an age-related switch in microglial function from phagocytic to more cytotoxic in vivo [16, 31].”
Hambali, A., Kumar, J., Hashim, N. F. M., Maniam, S., Mehat, M. Z., Cheema, M. S., Mustapha, M., Adenan, M. I., Stanslas, J., & Hamid, H. A. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.712317 · Cited by 65
“This switch coincided with excessive levels of soluble Aβ oligomers that produced deleterious effects on neuronal cells (Jimenez et al., 2008; Tang and Le, 2016).”
BackgroundLynch, M. A. (2013) · Immunology · doi:10.1111/imm.12156 · Cited by 64
The Role of Glial Cells in Synaptic Dysfunction: Insights into Alzheimer's Disease Mechanisms
Yu, Y., Chen, R., Mao, K., Deng, M., & Li, Z. (2023) · Aging and Disease · doi:10.14336/ad.2023.0718 · Cited by 62
“Microglia located around Aβ plaques have been found to exhibit an M2 phenotype, as indicated by Ym1, which reflects the fact that microglia can exert neuroprotective effects by degrading Aβ plaques [101].”
BackgroundInflammatory Risk Factors and Pathologies Associated with Alzheimers Disease
Sastre, M., Richardson, J. C., Gentleman, S., & Brooks, D. J. (2011) · Current Alzheimer Research · doi:10.2174/156720511795256062 · Cited by 59
Tang, S., Wang, X., Hong, H., Long, Y., Li, Y., Xiang, G., Jiang, L., Zhang, H., Liu, L., Miao, M., et al. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.08.026 · Cited by 61
Lee, D. C., Rizer, J., Hunt, J. B., Selenica, M. ‐. B., Gordon, M. N., & Morgan, D. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12002 · Cited by 57
Shin, J., Lee, J. K., Lee, J. E., Min, W., Schuchman, E. H., Jin, H. K., & Bae, J. (2011) · Stem Cells · doi:10.1002/stem.659 · Cited by 56
Interleukin-4 affects microglial autophagic flux
Tang, R.-H., Qi, R.-Q., & Liu, H.-Y. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.255975 · Cited by 59
“…Rapa: rapamycin autophagy induction, as a positive control; TGF-β: transforming growth factor β; ns: no significance. and phagocytic capability to a classically activated phenotype with amoebic appearance accompanied by secretion of inflammatory cytokines (Jimenez et al., 2008; Fan et al., 2017).”
BackgroundNSAIDs: how they work and their prospects as therapeutics in Alzheimer's disease
Sastre, M. (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00020 · Cited by 57
“Recently, these fi ndings have been backed up by observations indicating that microglia may change from alternative to classical phenotype over time (Colton et al., 2006; Hickman et al., 2008; Jimenez et al., 2008; Lucin and Wyss-Coray, 2009), although probably there is a heterogeneous population.”
Targeting gut microbiota to alleviate neuroinflammation in Alzheimer’s disease
Nguyen, V. T. T., & Endres, K. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114418 · Cited by 52
Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy
Hunt, J. B., Nash, K. R., Placides, D. S., Moran, P., Selenica, M. B., Abuqalbeen, F., Ratnasamy, K., Slouha, N., Ospina, S. R., Savlia, M., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.3959-14.2015 · Cited by 57
“…(both pro-inflammatory and anti-anti-inflammatory) in the brains of AD patients and amyloid- -depositing mice (Colton et al., 2006), whereas others report shifting from an alternative activation state to a classical activation state later in disease during amyloid deposition (Jimenez et al., 2008).”
BackgroundInfluentialOyanagi, K., Kinoshita, M., Suzuki‐Kouyama, E., Inoue, T., Nakahara, A., Tokiwai, M., Arai, N., Satoh, J., Aoki, N., Jinnai, K., et al. (2016) · Brain Pathology · doi:10.1111/bpa.12443 · Cited by 55
“In an AD mouse model, the APP 1 PS1 mouse, a distinctive shift from M2 to M1 activation in the brain has been observed (29).”
BackgroundImportance of GPCR-Mediated Microglial Activation in Alzheimer’s Disease
Haque, M. E., Kim, I., Jakaria, M., Akther, M., & Choi, D. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00258 · Cited by 55
“Age-dependent shifting of microglial phenotype from alternative to classical was associated with increased downregulation of the M2 phenotypic marker Ym1 and TNF-α release (Jimenez et al., 2008).”
BackgroundDisease-associated microglia in neurodegenerative diseases: Friend or foe?
Cheng, Y.-H., & Ho, M. S.-C. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3003426 · Cited by 57
“These microglia have high phagocytic activity and low expression of pro-inflammatory genes [97].”
Asai, H., Ikezu, S., Woodbury, M. E., Yonemoto, G., Cui, L., & Ikezu, T. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.11.026 · Cited by 49
Hracskó, Z., Baranyi, M., Csölle, C., Gölöncsér, F., Madarász, E., Kittel, Á., & Sperlágh, B. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-28 · Cited by 51
“[57] found that at early ages (4-6 months), activated microglia are restricted to amyloid deposits and are characterized by the absence of cytotoxic factors using a transgenic mouse model of Alzheimer’s disease.”
BackgroundBrain Inflammation Connects Cognitive and Non-Cognitive Symptoms in Alzheimer’s Disease
Sellés, M. C., Oliveira, M. M., & Ferreira, S. T. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179925 · Cited by 51
“Similar M1-M2 microglial dynamics was described by Jimenez et al. [178] in a transgenic mouse model of AD.”
T Cells—Protective or Pathogenic in Alzheimer’s Disease?
McManus, R. M., Mills, K. H. G., & Lynch, M. A. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9612-2 · Cited by 54
“This is associated with infiltration of peripheral cells, with age-related increased numbers of T cells and macrophages in the brain of APP/PS1 mice (Jimenez et al. 2008; Kelly et al. 2013; Minogue et al. 2014).”
BackgroundNanomaterials as Microglia Modulators in the Treatment of Central Nervous System Disorders
Battaglini, M., Marino, A., Montorsi, M., Carmignani, A., Ceccarelli, M. C., & Ciofani, G. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202304180 · Cited by 54
Williams, C. J., & Dexter, D. T. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12608 · Cited by 48
“Other studies suggest that microglia lose their protective properties in AD (Hickman et al. 2008; Jimenez et al. 2008).”
ResultEAAT expression by macrophages and microglia: still more questions than answers
Gras, G. S., Samah, B., Hubert, A., Léone, C., Porcheray, F., & Rimaniol, A. (2011) · Amino Acids · doi:10.1007/s00726-011-0866-6 · Cited by 48
“Likewise, in Alzheimer’s disease (AD) as well as in different transgenic models of AD, alternative activation markers are found expressed in response to amyloid plaques (Colton et al. 2006; Jimenez et al. 2008 ).”
BackgroundThe role of microRNAs in newborn brain development and hypoxic ischaemic encephalopathy
Ponnusamy, V., & Yip, P. K. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.11.041 · Cited by 47
Figueiredo, C. P., Bicca, M. A., Latini, A., Prediger, R. D., Medeiros, R., & Calixto, J. Β. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101320 · Cited by 47
“Some studies have shown that disruption of normal activity of mitochondrial respiratory chain complexes can be achieved by exposure to A [6, 70, 71].”
Insights on the Use of Transgenic Mice Models in Alzheimer’s Disease Research
Pádua, M. S., Guil-Guerrero, J. L., Prates, J. A. M., & Lopes, P. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052805 · Cited by 46
Smith, L. A., & McMahon, L. L. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.11.014 · Cited by 45
“Disease stage dependent switch in microglial function progresses from protective in early stages and damaging in later stages as shown in the PS1/APP mouse (Jimenez et al., 2008).”
Cu(II) enhances the effect of Alzheimer’s amyloid-β peptide on microglial activation
Yu, F., Gong, P., Hu, Z., Qiu, Y. L., Cui, Y., Gao, X., Chen, H., & Li, J. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0343-3 · Cited by 47
Drug Access to the Central Nervous System in Alzheimer’s Disease: Preclinical and Clinical Insights
Mehta, D. C., Short, J. L., Hilmer, S. N., & Nicolazzo, J. A. (2014) · Pharmaceutical Research · doi:10.1007/s11095-014-1522-0 · Cited by 47
Tang, S., Ji, M., Chen, L., Hu, M. Y., Long, Y., Li, Y., Miao, M., Li, J.-C., Li, N., Ji, H., et al. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713001314 · Cited by 43
Amyloidosis in Retinal Neurodegenerative Diseases
Masuzzo, A., Dinet, V., Cavanagh, C., Mascarelli, F., & Krantic, S. M. (2016) · Frontiers in Neurology · doi:10.3389/fneur.2016.00127 · Cited by 45
Trujillo‐Estrada, L., Jiménez, S., Castro, V. D., Torres, M., Baglietto‐Vargas, D., Moreno‐González, I., Navarro, V., Sanchez-Varo, R. M., Sánchez‐Mejías, E., Dávila, J. C., et al. (2013) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-1-73 · Cited by 44
“Retrotranscription (RT) was performed using random hexamers, 4 μg of total RNA as template and HighCapacity cDNA Archive Kit (Applied Biosystems) following the manufacturer recommendations [24,30].”
BackgroundMethodSelf-citationSerum perfluoroalkyl acids concentrations and memory impairment in a large cross-sectional study
Gallo, V., Leonardi, G. S., Brayne, C., Armstrong, B., & Fletcher, T. (2013) · BMJ Open · doi:10.1136/bmjopen-2012-002414 · Cited by 42
Nikodémová, M., Small, A. L., Kimyon, R. S., & Watters, J. J. (2016) · Physiological Genomics · doi:10.1152/physiolgenomics.00129.2015 · Cited by 46
Huang, C., Dong, D., Jiao, Q., Pan, H., Ma, L., & Wang, R. (2017) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12697 · Cited by 43
Ayton, S., Janelidze, S., Roberts, B. R., Palmqvist, S., Kalinowski, P., Diouf, I., Belaidi, A. A., Stomrud, E., Bush, A. I., & Hansson, O. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101904 · Cited by 43
Adenosine receptor signalling in Alzheimer’s disease
Trinh, P. N. H., Baltos, J., Hellyer, S. D., May, L. T., & Gregory, K. J. (2022) · Purinergic Signalling · doi:10.1007/s11302-022-09883-1 · Cited by 43
Carriba, P., Jiménez, S., Navarro, V., Moreno‐González, I., Barneda‐Zahonero, B., Moubarak, R. S., López‐Soriano, J., Gutiérrez, A., Vitórica, J., & Comella, J. X. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.6 · Cited by 40
“We have previously reported the presence of oligomeric Aβ (oAβ) in the soluble fractions of these transgenic animals.(32) According to this, in cultured neurons these soluble fractions also induced death (Figure 3c).”
BackgroundMethodInfluentialKoh, S.-H., Kwon, H. S., Choi, S. H., Jeong, J. H., Na, H. R., Lee, C. N., Yang, Y., Lee, A. Y., Lee, J.-H., Park, K. W., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00803-w · Cited by 39
“As the disease progresses, the microglia switch to a more neurotoxic phenotype [27, 28].”
Staging anti-inflammatory therapy in Alzheimer’s disease
Lichtenstein, M. P. (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00142 · Cited by 39
Interleukin-19 Acts as a Negative Autocrine Regulator of Activated Microglia
Horiuchi, H., Parajuli, B., Wang, Y., Azuma, Y., Mizuno, T., Takeuchi, H., & Suzumura, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0118640 · Cited by 40
“Activated microglia can exert either neurotoxic or neuroprotective effects, depending on their environmental conditions and the type and extent of stimulation [13–16], and can release both pro-inflammatory cytokines (e.”
BackgroundRodriguez, J. J., Noristani, H. N., & Verkhratsky, A. (2013) · Brain Structure and Function · doi:10.1007/s00429-013-0693-5 · Cited by 38
Interleukin-33 Protects Ischemic Brain Injury by Regulating Specific Microglial Activities
Luo, Q., Fan, Y., Lin, L., Wei, J., Li, Z., Li, Y., Nakae, S., Lin, W., & Chen, Q. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.05.047 · Cited by 41
Metadata
- Authors
- Jimenez, S., Baglietto-Vargas, D., Caballero, C., Moreno-Gonzalez, I., Torres, M., Sanchez-Varo, R., Ruano, D., Vizuete, M., Gutierrez, A., & Vitorica, J.
- Affiliations
- Universidad de Sevilla (ES)
- Universidad de Málaga (ES)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-11-05
- Volume
- 28
- Issue
- 45
- Pages
- 11650-11661
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6671312
- OpenAlex
- W2001334299
- Cited by
- 383
- References
- 70
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 19 · 2023: 14 · 2022: 19 · 2021: 30 · 2020: 22 · 2019: 21 · 2018: 19 · 2017: 20 · 2016: 19 · 2015: 26 · 2014: 28 · 2013: 37 · 2012: 25
- FWCI
- 12.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, cc-by-nc-nd)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, other-oa)
- Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by)
- Funders
- Ministerio de Economía y Competitividad
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Instituto de Salud Carlos III
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, microglial activation, alternative activation, hippocampus, amyloid-beta oligomers, soluble amyloid-beta, TNF-α, neurodegeneration, age-dependent disease progression, 6E10 antibody
- MeSH terms
- Aging, Alzheimer Disease, Analysis of Variance, Animals, Disease Models, Animal, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Inflammation, Mice, Transgenic, Mutation, Phenotype, Tumor Necrosis Factor-alpha, Amyloid beta-Protein Precursor, CD3 Complex, Microglia, Lectins, CD11b Antigen, Mice, Nitric Oxide Synthase Type II, Presenilin-1
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