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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
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769 · cited 2×
“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
Cited by
Sorted by citations
Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226
“With aging, A β - depositing mice increase in the expression of alternative activation state genes and deactivation state genes at the expense of classical activation state genes 220 , however see also 221 .”
Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes
Kwon, H. S., & Koh, S.-H. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00221-2 · Cited by 2,595
Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases
Tang, Y., & Le, W. (2016) · Molecular Neurobiology · doi:10.1007/s12035-014-9070-5 · Cited by 2,190
“seems to maintain even at relative old ages, suggesting that activated microglia surrounding Aβ plaques adopted an alternative phenotype, regardless of the age [92].”
BackgroundInfluentialNeuroinflammation and M2 Microglia: The Good, the Bad, and the Inflamed
Cherry, J. D., Olschowka, J. A., & O’Banion, M. K. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-98 · Cited by 1,748
“[132] observed at 6 months, when Aβ begins to accumulate in the APP/ PS1 Alzheimer’s disease mouse model, that there were YM1 cells present in the CNS; however, by 18 months YM1 mRNA levels decreased and there was a massive upregulation in inflammatory factors, suggesting a switch from M2 to M1 as pathology worsened […”
BackgroundNeuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice
Zhao, J., Bi, W., Xiao, S., Lan, X., Cheng, X., Zhang, J., Lu, D., Wei, W., Wang, Y., Li, H., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-42286-8 · Cited by 941
Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain
Colton, C. A. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9164-4 · Cited by 916
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870
Microglia and neurodegeneration: The role of systemic inflammation
Cunningham, C. (2013) · Glia · doi:10.1002/glia.22350 · Cited by 769
“phenotypes can shift from M2-type to more M1-like with advancing age in AD transgenics (Jimenez et al., 2008) it is clear that microglia are not operating in a fully M1”
BackgroundMicroglial dysfunction in brain aging and Alzheimer's disease
Mosher, K. I., & Wyss-Coray, T. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.008 · Cited by 618
“And still others have seen no significant age-related differences in microglial activation phenotypes when studied in the absence of any pathological insults [105,111].”
BackgroundIL-4 in the brain: a cytokine to remember
Gadani, S. P., Cronk, J. C., Norris, G. T., & Kipnis, J. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1202246 · Cited by 549
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 522
Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer’s disease
Kaur, D., Sharma, V., & Deshmukh, R. R. (2019) · Inflammopharmacology · doi:10.1007/s10787-019-00580-x · Cited by 503
Kitazawa, M., Cheng, D., Tsukamoto, M. R., Koike, M. A., Wes, P. D., Vasilevko, V., Cribbs, D. H., & LaFerla, F. M. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100620 · Cited by 473
“For example, aging itself triggers differential activation in microglia isolated from the APP/PS1 transgenic mouse model (54, 67).”
BackgroundMethodInflammation, microglia, and alzheimer's disease
Cameron, B., & Landreth, G. E. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.10.006 · Cited by 452
TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation
Liu, S., Liu, Y., Hao, W., Wolf, L., Kiliaan, A. J., Penke, B., Rübe, C. E., Walter, J., Heneka, M. T., Hartmann, T., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1101121 · Cited by 439
“During aging, M1 activation, but not M2 activation, can be further enhanced (48).”
BackgroundEstrogens, Neuroinflammation, and Neurodegeneration
Villa, A., Vegeto, E., Poletti, A., & Maggi, A. (2016) · Endocrine Reviews · doi:10.1210/er.2016-1007 · Cited by 423
Neuroinflammatory processes in Alzheimer’s disease
Heneka, M. T., O’Banion, M. K., Terwel, D., & Kummer, M. P. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0438-z · Cited by 433
“The ability of fibrillar Ab to trigger an inflammatory response is phenocopied in murine AD models that recapitulate Ab plaque formation (e.g. Matsuoka et al. 2001; Jimenez et al. 2008).”
BackgroundRegulation of microglial activation in stroke
Zhao, S.-C., Ma, L.-S., Chu, Z., Xu, H., Wu, W.-Q., & Liu, F. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2016.162 · Cited by 419
Michelucci, A., Heurtaux, T., Grandbarbe, L., Morga, E., & Heuschling, P. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.02.003 · Cited by 411
“Recently, Jimenez (Jimenez et al., 2008) shows 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 amicemodel of AD.”
BackgroundTomiyama, T., Matsuyama, S., Iso, H., Umeda, T., Takuma, H., Ohnishi, K., Ishibashi, K., Teraoka, R., Sakama, N., Yamashita, T., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5825-09.2010 · Cited by 396
“A oligomers have been demonstrated to cause these pathological changes in vitro when applied exogenously to cultured cells and brain slices (Hu et al., 1998; Lambert et al., 1998; Kayed et al., 2003; De Felice et al., 2008; Jimenez et al., 2008).”
BackgroundVarnum, M. M., & Ikezu, T. (2012) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-012-0181-2 · Cited by 412
“These include genes that repair damage to the extracellular matrix, such as arginase 1 (ARG1) (Gomi et al. 2011; Jimenez et al. 2008), mannose receptor (Akiyama et al. 2000), found in inflammatory zone 1, and chitinase 3-like 3 (YM1) (Colton et al. 2006a; Raes et al. 2002).”
BackgroundInfluentialMicroglia and Inflammation in Alzheimers Disease
Mandrekar-Colucci, S., & Landreth, G. E. (2010) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152710791012071 · Cited by 421
“[128] described an age-dependent switch in microglial activation in the hippocampus of the APP/PS1 mouse model.”
BackgroundMandrekar-Colucci, S., Karlo, J. C., & Landreth, G. E. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5268-11.2012 · Cited by 355
“While M2 gene expression has been detected in the AD brain, little is known about the mechanisms modulating this phenotypic conversion (Colton et al., 2006; Jimenez et al., 2008; Maier et al., 2008).”
BackgroundMicroglia and ischemic stroke: a double-edged sword.
Patel, A. R., Ritzel, R. M., McCullough, L. D., & Liu, F. (2013) · Europe PMC (PubMed Central) · Cited by 363
Microglia Function in Alzheimer’s Disease
Solito, E., & Sastre, M. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00014 · Cited by 361
“In addition, an increased risk of AD has been associated with several polymorphisms of pro-inflammatory genes, including IL-1 (Nicoll et al., 2000), IL-6 (Capurso et al., 2004), TNF-α (McCusker et al., 2001; Perry et al., 2001), and α1-antichymotrypsin (Kamboh et al., 1995).”
BackgroundChakrabarty, P., Jansen‐West, K., Beccard, A., Ceballos‐Diaz, C., Levites, Y., Verbeeck, C., Zubair, A. C., Dickson, D., Golde, T. E., & Das, P. (2010) · The FASEB Journal · doi:10.1096/fj.09-141754 · Cited by 328
“This is reminiscent of the establishment of an alternative macrophage M2 phenotype, albeit incomplete, described in PS1/APP mice where such plaque-associated microglia were shown to have beneficial phagocytic capabilities (22).”
BackgroundMethodInfluentialMicroglia Phenotypes in Aging and Neurodegenerative Diseases
Wendimu, M. Y., & Hooks, S. B. (2022) · Cells · doi:10.3390/cells11132091 · Cited by 336
“Jimenez et al. (2008) characterized age-dependent alteration of microglia phenotypes in the hippocampus of double PS1xAPP transgenic AD mice [260].”
BackgroundInflammation and Alzheimer’s disease
Lee, Y.-J., Han, S. B., Nam, S.-Y., Oh, K.-W., & Hong, J. T. (2010) · Archives of Pharmacal Research · doi:10.1007/s12272-010-1006-7 · Cited by 396
“Recently, these finding have been supported by studies indicating that microglia 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).”
BackgroundResultThe multifaceted profile of activated microglia
Lynch, M. A. (2009) · Molecular Neurobiology · doi:10.1007/s12035-009-8077-9 · Cited by 268
“However, recent evidence has suggested that there is an age-related switch in microglial function in the hippocampus of APP × PS1 transgenic mice from a phagocytic function to a more cytotoxic function which coincided with increased expression of Aβ42 [131].”
BackgroundImplications of glial nitric oxide in neurodegenerative diseases
Yuste, J. E., Tarragon, E., Campuzano, C. M., & Ros-Bernal, F. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00322 · Cited by 356
“Interestingly, NLRP3 is a modulator of IL-1β, a proinflammatory cytokine which production is also stimulated by the presence of Aβ plaques, together with other inflammatory markers, including IL-6 and tumor necrosis factor alpha (TNF-α; Jekabsone et al., 2006; Jimenez et al., 2008).”
BackgroundMicroglial phenotypes in Parkinson’s disease and animal models of the disease
Joers, V., Tansey, M. G., Mulas, G., & Carta, A. R. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.04.006 · Cited by 285
“Noteworthy, in Alzheimer's disease and in the elderly brain an imbalance of pro- and antiinflammatory microglia phenotypes have been reported (Hoozemans et al., 2006; Jimenez et al., 2008).”
BackgroundInfluentialMicroglia actions in Alzheimer's disease
Prokop, S., Miller, K. R., & Heppner, F. L. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1182-x · Cited by 291
“Although microglia express markers for both classical and alternative activation in AD [23], there seems to be a consensus that during the course of disease, similar to normal aging, microglia undergo a switch from a neuroprotective to a more classically activated phenotype at later stages of disease [69, 151].”
BackgroundLPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice
Lee, D. C., Rizer, J., Selenica, M.-L. B., Reid, P., Kraft, C., Johnson, A., Blair, L., Gordon, M. N., Dickey, C. A., & Morgan, D. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-56 · Cited by 293
“This raises questions regarding how particular M2 activation state markers are regulated by proinflammatory stimuli and why RNA and protein levels of YM1 are increased in AD patients and animal models of amyloid deposition, which are typically considered to be associated with a proinflammatory (M1) cytokine environmen…”
BackgroundInfluentialInflammatory responses in hypoxic ischemic encephalopathy
Liu, F., & McCullough, L. D. (2013) · Acta Pharmacologica Sinica · doi:10.1038/aps.2013.89 · Cited by 287
Lee, H. J., Lee, J. K., Lee, H.-W., Carter, J., Chang, J. W., Oh, W., Yang, Y. S., Suh, J., Lee, B., Jin, H. K., et al. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.03.024 · Cited by 291
“One study observed the exisence of an age-dependant phenotypic change of microglial ctivation in the hippocampus of an AD mouse model, from n alternative (expressing IL-4) activation state to a classic ytotoxic (expressing IL-1 and TNF- ) phenotype (Jimenez et al., 2008).”
BackgroundMaezawa, I., Zimin, P. I., Wulff, H., & Jin, L. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.135244 · Cited by 293
Pisanu, A., Lecca, D., Mulas, G., Wardas, J., Simbula, G., Spiga, S., & Carta, A. R. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.011 · Cited by 273
Losurdo, M., Pedrazzoli, M., D’Agostino, C., Elia, C., Massenzio, F., Lonati, E., Mauri, M., Rizzi, L., Molteni, L., Bresciani, E., et al. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.19-0327 · Cited by 272
“The increase of microglia number is typically observed in postmortem AD brains(90) and in AD preclinical models.(88,89,91) In our study, the presence of EVs”
BackgroundRole of Microglia in Neurological Disorders and Their Potentials as a Therapeutic Target
Du, L., Zhang, Y., Chen, Y., Zhu, J., Yang, Y., & Zhang, H.-L. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0245-0 · Cited by 280
“It was shown that microglia undergo a switch from a neuroprotective M2 to a more classically activated phenotype in the later stages of AD [131] [132].”
BackgroundKumar, A., Stoica, B. A., Sabirzhanov, B., Burns, M. P., Faden, A. I., & Loane, D. J. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.013 · Cited by 244
“Interestingly, a recent study demonstrated an agedependent phenotypic change of MG/MΦ activation in the hippocampus of AD transgenic (PS1M146L/APP751SL) mice from an M2 activation state with Aβ phagocytic capabilities to a M1 and neurotoxic phenotype, which promoted high levels of soluble Aβ oligomers and significant…”
BackgroundOntogeny and Polarization of Macrophages in Inflammation: Blood Monocytes Versus Tissue Macrophages
Dey, A., Allen, J., & Hankey-Giblin, P. A. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00683 · Cited by 254
“Similarly in a model of AD immune cell infiltration and localization of microglial populations in areas of amyloid β (Aβ) plaque deposits has been observed (69, 70).”
BackgroundMicroglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative
Navarro, V., Sanchez-Mejias, E., Jimenez, S., Muñoz-Castro, C., Sanchez-Varo, R., Davila, J. C., Vizuete, M., Gutierrez, A., & Vitorica, J. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00140 · Cited by 229
“We and others (Jimenez et al., 2008; Heneka et al., 2015) have previously described that this extensive Aβ accumulation was accompanied by intense local microglial activation (see Figures 1A,B).”
BackgroundMethodInfluentialSelf-citationSanchez-Varo, R., Trujillo-Estrada, L., Sanchez-Mejias, E., Torres, M., Baglietto-Vargas, D., Moreno-Gonzalez, I., De Castro, V., Jimenez, S., Ruano, D., Vizuete, M., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-011-0896-x · Cited by 222
“The A11 or 6E10 immunoprecipitation experiments were also performed as described in detail previously [29, 30].”
BackgroundMethodResultInfluentialSelf-citationChoi, S., Aïd, S., Kim, H., Jackson, S. H., & Bosetti, F. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07572.x · Cited by 228
“alternative activation state with Ab phagocytic capabilities to a classical cytotoxic phenotype, which promotes high levels of soluble Ab oligomers and significant pyramidal neurodegeneration (Jimenez et al. 2008).”
InfluentialSexually divergent induction of microglial-associated neuroinflammation with hippocampal aging
Mangold, C. A., Wronowski, B., Du, M., Masser, D. R., Hadad, N., Bixler, G. V., Brucklacher, R. M., Ford, M. M., Sonntag, W. E., & Freeman, W. M. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0920-8 · Cited by 203
“activated microglia phenotypes occurs between the beginning of Aβ pathology (alternative phenotype) and advanced stages (classical phenotype), the latter of which may cause disease-associated neuron loss [57].”
BackgroundPhagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease
Gomez‐Arboledas, A., Davila, J. C., Sanchez‐Mejias, E., Navarro, V., Nuñez‐Diaz, C., Sanchez‐Varo, R., Sanchez‐Mico, M. V., Trujillo‐Estrada, L., Fernandez‐Valenzuela, J. J., Vizuete, M., et al. (2018) · Glia · doi:10.1002/glia.23270 · Cited by 220
“…of both the transgenic APP/PS1 model and Alzheimer’s patients (Braak V–VI) displays significant astrogliosis (measured by GFAP expression and by the area covered by the reactive astrocytes; see also Jimenez et al., 2008), which progresses in parallel to the extracellular amyloid pathology.”
BackgroundInfluentialSelf-citationFingolimod phosphate promotes the neuroprotective effects of microglia
Noda, H., Takeuchi, H., Mizuno, T., & Suzumura, A. (2013) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.12.005 · Cited by 215
“Activatedmicroglia can be neurotoxic or neuroprotective depending on the conditions, including the nature of any stimuli, degree of stimulation, spatiotemporal distribution, and age of the subject (Jimenez et al., 2008; Wu et al., 2008b; Nakanishi and Wu, 2009; Sawada, 2009).”
Inflammation Induced by Infection Potentiates Tau Pathological Features in Transgenic Mice
Sy, M., Kitazawa, M., Medeiros, R., Whitman, L., Cheng, D., Lane, T. E., & LaFerla, F. M. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.02.012 · Cited by 210
“The immune responses are altered and become dysfunctional during aging.(55) Therefore, infectious agents may not be as detrimental in young individuals when the immune responses can be properly regulated, but this becomes more deleterious in older individuals.”
BackgroundChakrabarty, 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
“However, analysis of two alternative “M2” microglial phenotype markers, Ym-1 and Arg, that have been recently reported as potential markers for enhanced microglia-mediated Ab phagocytosis (40, 41) showed that these were unchanged in mIFN-g–expressing”
BackgroundMethodResultInfluentialDeep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice
Wang, L., Zhang, Y., Zhao, Y., Marshall, C., Wu, T., & Xiao, M. (2019) · Brain Pathology · doi:10.1111/bpa.12656 · Cited by 199
Traumatic Brain Injury Induces Tau Aggregation and Spreading
Edwards, G., Zhao, J., Dash, P. K., Soto, C., & Moreno-Gonzalez, I. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2018.6348 · Cited by 195
Pan, J., Jin, J., Ge, H. M., Yin, K., Chen, X. '., Han, L., Chen, Y., Qian, L., Li, X., & Xu, Y. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0270-3 · Cited by 192
“PPARγ activation is positively related to ameliorating experimental autoimmune encephalomyelitis (EAE) in mice [28] and reducing amyloid deposition along with improving cognitive function in Alzheimer’s disease models [29].”
BackgroundInfluentialJiménez, S., Torres, M., Vizuete, M., Sanchez-Varo, R. M., Sánchez‐Mejías, E., Trujillo‐Estrada, L., Carmona‐Cuenca, I., Caballero, C., Ruano, D., Gutiérrez, A., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.209718 · Cited by 190
Self-citationDupont, A.-C., Largeau, B., Santiago Ribeiro, M., Guilloteau, D., Tronel, C., & Arlicot, N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040785 · Cited by 182
“This Aβ-induced inflammatory environment [126], combined with effect of immunosenescence on microglia [127,128], lead to a situation in which microglia that initially exhibited a neuroprotective M2 phenotype at the beginning of AD [129], become confined to a classical activated state (i.”
BackgroundKitazawa, M., Medeiros, R., & M. LaFerla, F. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212799315786 · Cited by 178
“However, in APP/PS1 transgenic mouse model, aging significantly influences the activation status of microglia, suggesting that it may exacerbate the progression of AD-related neuropathology [159].”
BackgroundMicroglial Phenotype and Adaptation
Eggen, B. J. L., Raj, D. D. A., Hanisch, U., & Boddeke, H. W. G. M. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9490-4 · Cited by 187
Ferretti, M. T., Merlini, M., Späni, C. B., Gericke, C., Schweizer, N., Enzmann, G. U., Engelhardt, B., Kulic, L., Suter, T. B., & Nitsch, R. M. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.02.009 · Cited by 180
Dirscherl, K., Karlstetter, M., Ebert, S., Kraus, D., Hlawatsch, J., Walczak, Y., Moehle, C., Fuchshofer, R., & Langmann, T. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-3 · Cited by 175
“Nevertheless, recent findings from in vitro cultures of the murine microglial cell line MMGT12 [23] and hippocampal microglia from the PS1xAPP Alzheimer’s mouse model [24] implicate that microglia have the ability to differentiate into M1 and M2 polarized phenotypes.”
Jin, M., Xu, R., Wang, L., Alam, M. M., Ma, Z., Zhu, S., Martini, A. C., Jadali, A., Bernabucci, M., Xie, P., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.06.007 · Cited by 174
Tammineni, P., Ye, X., Feng, T., Aikal, D., & Cai, Q. (2017) · eLife · doi:10.7554/elife.21776 · Cited by 175
“…the association of Ab oligomers with AVs in AD brains, we utilized the well-characterized A11 antibody that only recognizes soluble Ab oligomers, but not APP and its cleaved products C99, soluble monomer, or insoluble fibrils (Jimenez et al., 2008, 2011; Kayed et al., 2003; Zempel et al., 2010).”
MethodBurke, N. N., Kerr, D. M., Moriarty, O., Finn, D. P., & Roche, M. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.06.015 · Cited by 170
Efficient isolation of live microglia with preserved phenotypes from adult mouse brain
Nikodémová, M., & Watters, J. J. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-147 · Cited by 165
“Microglia play a key role in the neuroinflammation associated with many neurodegenerative, ischemic, and traumatic disorders [4-12].”
BackgroundMedeiros, R., Kitazawa, M., Passos, G. F., Baglietto-Vargas, D., Cheng, D., Cribbs, D. H., & LaFerla, F. M. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.01.051 · Cited by 163
Self-citationMartin, E., Boucher, C., Fontaine, B., & Delarasse, C. (2017) · Aging Cell · doi:10.1111/acel.12522 · Cited by 156
“We found consistent results with those determined at the mRNA level for increased expression of IL-1b, TNF-a, CCL-3, and iNOS (Hickman et al., 2008; Jimenez et al., 2008; Minogue et al., 2014; Babcock et al., 2015), but we observed differences for IL-4, IL-10, and CD36 previously shown to be decreased (Hickman et al.”
BackgroundResultInfluentialMicroglia Demonstrate Age-Dependent Interaction with Amyloid-β Fibrils
Floden, A. M., & Combs, C. K. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101014 · Cited by 166
“In agreement with this notion, a prior study has demonstrated that wild type microglia undergo an increase in mRNA levels of YM-1, an alternative activation marker, from 6 to 18 months of age while a transgenic AD line expressing human mutant APP and PS1 demonstrated significantly higher levels of YM-1 mRNA compared t…”
Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration
Sanchez-Mejias, E., Navarro, V., Jimenez, S., Sanchez-Mico, M., Sanchez-Varo, R., Nuñez-Diaz, C., Trujillo-Estrada, L., Davila, J. C., Vizuete, M., Gutierrez, A., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1630-5 · Cited by 175
“Primary murine microglial or astroglial cultures were performed as previously described [22].”
BackgroundMethodInfluentialSelf-citationMicroglia activation states and cannabinoid system: Therapeutic implications
Mecha, M., Carrillo-Salinas, F. J., Feliú, A., Mestre, L., & Guaza, C. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.06.011 · Cited by 165
“…illustrated that APP/PS1 mice, a transgenic mouse model of AD, shift from an M2 profile early on in the disease towards an M1 response after 18 months of pathogenesis, which is concomitant with a downregulation of the M2 marker Ym1 and upregulation of inflammatory factors (Jimenez et al., 2008).”
BackgroundCai, M., Lee, J., & Yang, E. J. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1665-3 · Cited by 163
Liu, Y., Holdbrooks, A. T., Sarno, P. D., Rowse, A. L., Yanagisawa, L. L., McFarland, B. C., Harrington, L. E., Raman, C., Sabbaj, S., Benveniste, E. N., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301513 · Cited by 155
Andersen, H. H., Johnsen, K. B., & Moos, T. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1509-8 · Cited by 151
“However, evidence from transgenic Alzheimer’s disease mice suggests that a phenotypic shift from M2 to M1 microglia occurs in models of prolonged neuroinflammation potentially aggravating neuronal degeneration with increasing age [46].”
BackgroundEvans, C. E., Miners, J. S., Piva, G., Willis, C. L., Heard, D. M., Kidd, E. J., Good, M. A., & Kehoe, P. G. (2020) · Acta Neuropathologica · doi:10.1007/s00401-019-02098-6 · Cited by 145
Laurindo, L. F., Dias, J. A., Araújo, A. C., Pomini, K. T., Galhardi, C. M., Detregiachi, C. R. P., Haber, L. S. D. A., Roque, D. D., Bechara, M. D., de Castro, M. V. M., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1305933 · Cited by 156
Glial cells in Alzheimer’s disease: From neuropathological changes to therapeutic implications
Uddin, M. S., & Lim, L. W. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101622 · Cited by 154
Zhao, Q., Wu, X., Yan, S., Xie, X., Fan, Y., Zhang, J., Peng, C. Y., & You, Z. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0728-y · Cited by 142
Klein, W. L. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129039 · Cited by 145
“This would be consistent with numerous in vitro studies such as those detailed earlier, as well as others showing that exogenously applied A oligomers activate astrocytes [106] and microglia [107], impair axonal transport [83], and cause selective neuronal death ([12]; see review by Ferreira and Klein [22]).”
Ma, T., Gong, K., Ao, Q., Yan, Y., Song, B., Huang, H., Zhang, X., & Gong, Y. (2013) · Cell Transplantation · doi:10.3727/096368913x672181 · Cited by 146
What is microglia neurotoxicity (Not)?
Biber, K. P. H., Owens, T., & Boddeke, E. (2014) · Glia · doi:10.1002/glia.22654 · Cited by 146
“An age-dependent phenotypic shift from M2 to M1-like microglia might occur in mouse models of AD, such as APP/PS1, owing to accumulation of soluble Ab oligomers and neuronal loss (Jimenez et al., 2008).”
BackgroundXu, Y., Xu, Y., Wang, Y., Wang, Y., He, L., Jiang, Z., Huang, Z., Liao, H., Li, J., Saavedra, J. M., et al. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.07.015 · Cited by 140
“inflammatory diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, traumatic brain injury and stroke (Hu et al., 2012; Jimenez et al., 2008; Perry et al., 2010), and the incidence and development of these diseases also accompanied”
BackgroundDifferential cell proliferation in the cortex of the appsweps1de9 alzheimer's disease mouse model
Kamphuis, W., Orre, M., Kooijman, L., Dahmen, M., & Hol, E. M. (2012) · Glia · doi:10.1002/glia.22295 · Cited by 137
The Role of Neuroinflammation in Dementias
Pasqualetti, G., Brooks, D. J., & Edison, P. (2015) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-015-0531-7 · Cited by 133
Park, J., Ha, H.-J., Chung, E. S., Baek, S. H., Cho, Y., Kim, H. K., Han, J., Sul, J. H., Lee, J., Kim, E., et al. (2021) · Science Advances · doi:10.1126/sciadv.abd3207 · Cited by 139
Neuroinflammation in neurological disorders: pharmacotherapeutic targets from bench to bedside
Mishra, A., Bandopadhyay, R., Singh, P. K., Mishra, P. S., Sharma, N., & Khurana, N. (2021) · Metabolic Brain Disease · doi:10.1007/s11011-021-00806-4 · Cited by 134
Tao, L., Liu, Q., Zhang, F., Fu, Y., Zhu, X. D., Weng, X., Han, H., Huang, Y., Suo, Y., Chen, L., et al. (2021) · Light Science & Applications · doi:10.1038/s41377-021-00617-3 · Cited by 133
Respiratory infection promotes T cell infiltration and amyloid-β deposition in APP/PS1 mice
McManus, R. M., Higgins, S. C., Mills, K. H. G., & Lynch, M. A. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.07.025 · Cited by 134
“Interestingly CD3þ cells have been identified in brain tissue prepared from 18-month-old, but not 6-month-old, APP/PS1 mice (Jimenez et al., 2008).”
BackgroundChoi, S., Aïd, S., Caracciolo, L., Minami, S., Niikura, T., Matsuoka, Y., Turner, R. S., Mattson, M. P., & Bosetti, F. (2012) · Journal of Neurochemistry · doi:10.1111/jnc.12059 · Cited by 136
“It seems that, as AD progresses, microglia change toward a pro-inflammatory phenotype and lose their Ab-clearing activities, resulting in reduced Ab uptake and degradation (Jimenez et al. 2008).”
BackgroundInfluentialBhalala, U. S., Koehler, R. C., & Kannan, S. (2015) · Frontiers in Pediatrics · doi:10.3389/fped.2014.00144 · Cited by 133
“Depending on the type of insult, the phenotype of microglial activation switches over time from M1 to M2 or vice versa (111).”
BackgroundSARS-CoV-2 Spike Glycoprotein S1 Induces Neuroinflammation in BV-2 Microglia
Olajide, O. A., Iwuanyanwu, V. U., Adegbola, O. D., & Al‐Hindawi, A. A. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02593-6 · Cited by 124
Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review
Edler, M. K., Mhatre-Winters, I., & Richardson, J. R. (2021) · Cells · doi:10.3390/cells10051138 · Cited by 126
Zhang, F., Zhong, R., Li, S., Fu, Z., Cheng, C., Cai, H., & Le, W. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00282 · Cited by 128
“In AD, microglia surrounding and infiltrating the Aβ plaques are generally activated as YM-1 positive M2 phenotype (Jimenez et al., 2008).”
BackgroundNeuroinflammatory Signals in Alzheimer Disease and APP/PS1 Transgenic Mice
López‐González, I., Schlüter, A., Aso, E., Garcia‐Esparcia, P., Ansoleaga, B., Llorens, F., Carmona, M., Moreno, J. R., Fuso, A., Portero‐Otín, M., et al. (2015) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000176 · Cited by 128
Takeuchi, H., & Suzumura, A. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00189 · Cited by 127
“Therefore, whether activated microglia exert a neurotoxic or a neuroprotective effect may depend on their environment, the spatiotemporal distribution of the microglia themselves, and the type and magnitude of stimuli (Jimenez et al., 2008; Wu et al., 2008; Nakanishi and Wu, 2009; Sawada, 2009).”
Nicotinic Acetylcholine Receptor Agonists for the Treatment of Alzheimer’s Dementia: An Update
Hoskin, J. L., Al-Hasan, Y. M., & Sabbagh, M. N. (2018) · Nicotine & Tobacco Research · doi:10.1093/ntr/nty116 · Cited by 128
Mei, X., Ezan, P., Giaume, C., & Koulakoff, A. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.08.001 · Cited by 119
Lee, H. G., Won, S. M., Gwag, B. J., & Lee, Y. B. (2011) · Experimental & Molecular Medicine · doi:10.3858/emm.2011.43.1.001 · Cited by 122
“Recently, soluble oligomers of Aβ have been suggested as potent stimulators of microglial activation (Hashioka et al., 2005; Jimenez et al., 2008), although most studies have considered fAβ to be a more powerful stimulus (McDonald et al., 1997; Combs et al., 2001).”
BackgroundLee, J. K., Schuchman, E. H., Jin, H. K., & Bae, J. (2012) · Stem Cells · doi:10.1002/stem.1125 · Cited by 121
P2X7 Receptor Signaling Pathway as a Therapeutic Target for Neurodegenerative Diseases
Takenouchi, T., Sekiyama, K., Sekigawa, A., Fujita, M., Waragai, M., Sugama, S., Iwamaru, Y., Kitani, H., & Hashimoto, M. (2010) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-010-0069-y · Cited by 118
“At an early age (4–6 months), activated microglia are restricted to amyloid deposits and characterized by the absence of cytotoxic factors (Jimenez et al. 2008).”
BackgroundHan, H., Zhao, Y., Du, J., Wang, S., Yang, X., Li, W., Song, J., Zhang, S., Zhang, Z., Tan, Y., et al. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00390-4 · Cited by 122
“In AD patients, the alternative activation of microglia appears to be inhibited favoring classical activation [85].”
BackgroundInfection, systemic inflammation, and Alzheimer's disease
Lim, S., Rodríguez‐Ortiz, C. J., & Kitazawa, M. (2015) · Microbes and Infection · doi:10.1016/j.micinf.2015.04.004 · Cited by 117
The anti-inflammatory Annexin A1 induces the clearance and degradation of the amyloid-β peptide
Ries, M., Loiola, R. A., Shah, U. N., Gentleman, S., Solito, E., & Sastre, M. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0692-6 · Cited by 106
“inflammatory molecules [33, 34] and increasing Aβ phagocytosis.”
Minogue, A. M., Jones, R. S., Kelly, R. J., McDonald, C., Connor, T. J., & Lynch, M. A. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.12.026 · Cited by 112
“Although recent evidence has indicated that microglia surrounding Ab deposits in APP/PS1 mice may be alternatively activated and those distal to the deposits are classically activated in older animals (Jimenez et al., 2008), the effect of activation state on the capacity of microglia to phagocytose Ab remains to be cl…”
Background
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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