Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease
Open accessAbstract
• Introduction • Innate immune response in the AD brain - Microglia - Astrocyte • Glial cells mediate the peripheral immune response in AD - Glial cell interaction with endothelial cells - Glial cell interaction with T cells • Glial cell activation as a therapeutic target in AD • Conclusion Alzheimer's disease (AD) affects more than 18 million people worldwide and is characterized by progressive memory deficits, cognitive impairment and personality changes. The main cause of AD is generally attributed to the increased production and accumulation of amyloid-β (Aβ), in association with neurofibrillary tangle (NFT) formation. Increased levels of pro-inflammatory factors such as cytokines and chemokines, and the activation of the complement cascade occurs in the brains of AD patients and contributes to the local inflammatory response triggered by senile plaque. The existence of an inflammatory component in AD is now well known on the basis of epidemiological findings showing a reduced prevalence of the disease upon long-term medication with anti-inflammatory drugs, and evidence from studies of clinical materials that shows an accumulation of activated glial cells, particularly microglia and astrocytes, in the same areas as amyloid plaques. Glial cells maintain brain plasticity and protect the brain for functional recovery from injuries. Dysfunction of glial cells may promote neurodegeneration and, eventually, the retraction of neuronal synapses, which leads to cognitive deficits. The focus of this review is on glial cells and their diversity properties in AD.
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IFN-γ up-regulates the expression of major histocompatibility complex class II molecules by microglial cells.
“T-helper 1 cells can promote microglial cell activation through the secretion of IFN-γ, which also up-regulates the expression major histocompatibility complex class II molecules by microglial cells, thereby enhancing the interaction between T cells and microglial cells [164, 165].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [164]
T-helper 1 cells can promote microglial cell activation through the secretion of IFN-γ.
“T-helper 1 cells can promote microglial cell activation through the secretion of IFN-γ, which also up-regulates the expression major histocompatibility complex class II molecules by microglial cells, thereby enhancing the interaction between T cells and microglial cells [164, 165].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [164]
Glial cells can mediate the permeability of the blood brain barrier to recruit specialized immune cells from the periphery such as T cells.
“It is also known that glial cells can mediate the permeability of blood brain barrier to recruit specialized immune cells from the periphery such as T cells [164].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [164]
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BackgroundInterleukin-1, neuroinflammation, and Alzheimer's disease
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“Pro-inflammatory cytokines, such as interleukin1 (IL-1 / [36, 37], tumour necrosis factor- (TNF- ) [38] and IL-6 [39], may play an important role in AD pathology and lead to an increased production of inducible nitric oxide synthase (iNOS), neuronal stress and further neuronal dysfunction and death [40].”
BackgroundAbsence of C1q Leads to Less Neuropathology in Transgenic Mouse Models of Alzheimer's Disease
Fonseca, M. I., Zhou, J., Botto, M., & Tenner, A. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0901-04.2004 · Cited by 345 · cited 1× · see citing works
“Furthermore, the absence of C1q leads to less neuropathology in transgenic mouse models of AD [28].”
BackgroundComplement components of the innate immune system in health and disease in the CNS
Gasque, P., Dean, Y. D., McGreal, E. P., VanBeek, J., & Morgan, B. P. (2000) · Immunopharmacology · doi:10.1016/s0162-3109(00)80302-1 · Cited by 343 · cited 3× · see citing works
“The complement system provides an innate immune response against pathogenic features and contributes to the local inflammatory response triggered by A deposition and NFT in AD [17, 22].”
BackgroundJantzen, P. T., Connor, K. E., DiCarlo, G., Wenk, G. L., Wallace, J. L., Rojiani, A. M., Coppola, D., Morgan, D., & Gordon, M. N. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-06-02246.2002 · Cited by 337 · cited 1× · see citing works
“In support of this, Jantzen and colleagues [127] suggest that microglial activation may be beneficial based on results of their studies of a nitric oxide-releasing NSAID, NCX-2216.”
BackgroundImmunology and immunotherapy of Alzheimer's disease
Weiner, H. L., & Frenkel, D. (2006) · Nature Reviews Immunology · doi:10.1038/nri1843 · Cited by 335 · see citing works
Self-citationMicroglia and Alzheimer's disease pathogenesis
Streit, W. J. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20093 · Cited by 335 · cited 4× · see citing works
“Microglia accumulate in plaques containing A fibrils, but not in plaques containing amorphous non-fibrillar amyloid [47].”
BackgroundInfluentialUp-Regulated Production and Activation of the Complement System in Alzheimer's Disease Brain
Yasojima, K., Schwab, C., McGeer, E. G., & McGeer, P. L. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65340-0 · Cited by 328 · cited 1× · see citing works
“hippocampus and cortex), C1q mRNA level is increased up to 80-fold compared to control levels [27].”
BackgroundRole of complement in neurodegeneration and neuroinflammation
Bonifati, D. M., & Kishore, U. (2006) · Molecular Immunology · doi:10.1016/j.molimm.2006.03.007 · Cited by 310 · cited 2× · see citing works
“The complement system provides an innate immune response against pathogenic features and contributes to the local inflammatory response triggered by A deposition and NFT in AD [17, 22].”
BackgroundHeneka, M. T., Sastre, M., Dumitrescu-Ozimek, L., Dewachter, I., Walter, J., Klockgether, T., & Van Leuven, F. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-22 · Cited by 309 · cited 1× · see citing works
“It is possible, however, that small soluble aggregates of A trigger local activation of glial cells, as suggested by a recent study of the young thymus cell antigen 1 (Thy1)-APP mice that had not yet developed A deposits [48].”
The LPS receptor (CD14) links innate immunity with Alzheimer's disease
Fassbender, K., Walter, S., Kühl, S., Landmann, R., Ishii, K., Bertsch, T., Stalder, A. K., Muehlhauser, F., Liu, Y., Ulmer, A. J., et al. (2004) · The FASEB Journal · doi:10.1096/fj.03-0364fje · Cited by 307 · see citing works
Toll‐like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators
Bsibsi, M., Persoon-Deen, C., Verwer, R. W. H., Meeuwsen, S., Ravid, R., & van Noort, J. M. (2006) · Glia · doi:10.1002/glia.20328 · Cited by 296 · see citing works
Advanced glycation endproducts in ageing and Alzheimer's disease
Münch, G. W., Thome, J., Foley, P. B., Schinzel, R., & Riederer, P. F. (1997) · Brain Research Reviews · doi:10.1016/s0165-0173(96)00016-1 · Cited by 275 · cited 14× · see citing works
“Lue LF,Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM, Stern DM, Yan SD. Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism.”
BackgroundInfluentialAmyloid β42Activates a G-Protein-Coupled Chemoattractant Receptor, FPR-Like-1
Le, Y., Gong, W., Tiffany, H. L., Tumanov, A. V., Nedospasov, S. A., Shen, W., Dunlop, N. M., Gao, J., Murphy, P. M., Oppenheim, J. J., et al. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-02-j0003.2001 · Cited by 272 · see citing works
Evidence That Aging And Amyloid Promote Microglial Cell Senescence
Flanary, B. E., Sammons, N. W., Nguyen, C., Walker, D., & Streit, W. J. (2007) · Rejuvenation Research · doi:10.1089/rej.2006.9096 · Cited by 272 · cited 2× · see citing works
“Furthermore, a recent study reports that microglial cells exhibit significant telomere shortening and a reduction of telomerase activity in normal aging rats [66], and that in humans there is a tendency toward microglial cell telomere shortening with a presence of dementia [66].”
BackgroundChemokines/chemokine receptors in the central nervous system and Alzheimer's disease
Xia, M., & Hyman, B. T. (1999) · Journal of NeuroVirology · doi:10.3109/13550289909029743 · Cited by 269 · cited 2× · see citing works
“Several chemokines and chemokine receptors have been found to be up-regulated in the AD brain [32].”
BackgroundXia, M. Q., Bacskai, B. J., Knowles, R. B., Qin, S. X., & Hyman, B. T. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(00)00285-x · Cited by 269 · see citing works
Sheng, J. G., Ito, K., Skinner, R. D., Mrak, R. E., Rovnaghi, C. R., van Eldik, L. J., & Griffin, W. S. T. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00104-2 · Cited by 269 · cited 3× · see citing works
“Edwards MM, Robinson SR. TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer’s disease.”
BackgroundXia, M., Qin, S., Wu, L.-J., Mackay, C., & Hyman, B. (1998) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65542-3 · Cited by 267 · see citing works
Astrocytes Regulate Microglial Phagocytosis of Senile Plaque Cores of Alzheimer's Disease
DeWitt, D. A., Perry, G., Cohen, M., Doller, C., & Silver, J. (1998) · Experimental Neurology · doi:10.1006/exnr.1997.6738 · Cited by 261 · cited 1× · see citing works
“In AD, activated astrocytes can contain A fragments, providing further evidence of their role in A degradation [90].”
BackgroundMicroglia and neuroprotection: implications for Alzheimer's disease
Streit, W. J. (2005) · Brain Research Reviews · doi:10.1016/j.brainresrev.2004.12.013 · Cited by 256 · cited 1× · see citing works
“In addition to their innate ability to phagocytose and clear A , glial cells can also be activated to promote the clearance of A and prevent neuronal death in AD [65, 117, 122, 123] (Table 1).”
BackgroundInflammation and therapeutic vaccination in CNS diseases
Weiner, H. L., & Selkoe, D. J. (2002) · Nature · doi:10.1038/nature01325 · Cited by 253 · see citing works
Shen, M. M., & Leder, P. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.17.8240 · Cited by 250 · see citing works
Simone, R. D., Ajmone‐Cat, M. A., Carnevale, D., & Minghetti, L. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-4 · Cited by 248 · see citing works
ISHIZUKA, K., KIMURA, T., IGATA‐YI, R., KATSURAGI, S., TAKAMATSU, J., & MIYAKAWA, T. (1997) · Psychiatry and Clinical Neurosciences · doi:10.1111/j.1440-1819.1997.tb02375.x · Cited by 245 · cited 4× · see citing works
“Furthermore, an astrocytic response to IL-1 and TNF- results in an elevation of colony stimulating factor 1 (CSF-1) [86], granulocyte-macrophage CSF (GM-CSF) [86], granulocyte CSF (G-CSF) [86], MCP-1 and MIP-1 [33, 87], which can lead to the recruitment of microglial cells to A plaques [88].”
BackgroundInfluentialDifferences in the Mode of Phagocytosis with Fc and C3 Receptors in Macrophages
Kaplan, G. (1977) · Scandinavian Journal of Immunology · doi:10.1111/j.1365-3083.1977.tb02153.x · Cited by 244 · cited 1× · see citing works
“Engagement of the FcR by immune IgG initiates phagocytosis [117, 128, 129], which is characterized by an extension of pseudopodia and an envelopment of the phagocytic target by a mechanism of tyrosine kinases, Rac and Cdc42 [130].”
BackgroundDeane, R., Sagare, A. P., Hamm, K., Parisi, M., LaRue, B., Guo, H., Wu, Z., Holtzman, D. M., & Zloković, B. V. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3697-05.2005 · Cited by 233 · see citing works
Aharoni, R., Kayhan, B., Eilam, R., Sela, M., & Arnon, R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2336171100 · Cited by 233 · cited 1× · see citing works
“Recent reports [143, 144] suggest that this can be achieved in APP-transgenic mice by immunizing them with glatiramer acetate (GA) [145], which is a random amino acid copolymer of alanine, lysine, glutamic acid and tyrosine used for the treatment of multiple sclerosis that induces both Th2- and Th3-cell response.”
BackgroundIntrahippocampal LPS injections reduce Aβ load in APP+PS1 transgenic mice
DiCarlo, G. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00292-5 · Cited by 223 · see citing works
Glial activation in Alzheimer's disease: the role of Aβ and its associated proteins
Meda, L. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00307-4 · Cited by 222 · cited 1× · see citing works
“Astrocyte activation seems to be particularly prominent around A deposits both in the brain parenchyma and in the cerebrovasculature [63].”
BackgroundVulih-Shultzman, I., Pinhasov, A., Mandel, S., Grigoriadis, N., Touloumi, O., Pittel, Z., & Gozes, I. (2007) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.129551 · Cited by 219 · cited 3× · see citing works
“Research of the activity-dependent neuroprotective protein (ADNP), a gene product essential for brain formation, shows that ADNP knockout is embryonic lethal and that an ADNP partial deficiency results in cognitive deficits that are paralleled by tau hyperphosphorylation [162].”
BackgroundMethodTherapies for Alzheimer's disease
Melnikova, I. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2314 · Cited by 219 · cited 2× · see citing works
“Journal compilation © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd phase II clinical trial of patients with AD [137, 138].”
BackgroundIncreased S100β neurotrophic activity in Alzheimer's disease temporal lobe
Marshak, D. R., Pesce, S. A., Stanley, L. C., & Griffin, W. S. T. (1992) · Neurobiology of Aging · doi:10.1016/0197-4580(92)90002-f · Cited by 218 · see citing works
Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice
Tan, J., Town, T., Crawford, F., Mori, T., DelleDonne, A., Crescentini, R., Obregon, D., Flavell, R. A., & Mullan, M. J. (2002) · Nature Neuroscience · doi:10.1038/nn968 · Cited by 217 · cited 3× · see citing works
“This finding suggests several possible mechanisms underlying mitigation of AD pathology in response to CD40L and validates the CD40–CD40L interaction as a target for therapeutic intervention in AD [54, 118] (Table 1).”
BackgroundChen, K., Iribarren, P., Hu, J., Chen, J., Gong, W., Cho, E. H., Lockett, S., Dunlop, N. M., & Wang, J. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m508125200 · Cited by 214 · see citing works
Amyloid-β Immunization Effectively Reduces Amyloid Deposition in FcRγ-/-Knock-Out Mice
Das, P., HOWARD, V. G., Loosbrock, N., Dickson, D. W., Murphy, M. P., & Golde, T. E. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-24-08532.2003 · Cited by 212 · see citing works
The role of complement and activated microglia in the pathogenesis of Alzheimer's disease
Eikelenboom, P., & Veerhuis, R. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00108-x · Cited by 206 · cited 1× · see citing works
“Furthermore, A fibril interacts with numerous microglial membrane receptors including scavenger receptor A (SRA) [20, 52] and B [20], CD36 [53], CD40 [54], 6/ 1 integrinCD36-CD47 complex [55] and complement receptors [56] (Table 1).”
BackgroundWilcock, D. M., Munireddy, S. K., Rosenthal, A., Ugen, K. E., Gordon, M. N., & Morgan, D. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.09.015 · Cited by 202 · see citing works
Eckman, C. B., & Eckman, E. A. (2005) · Biochemical Society Transactions · doi:10.1042/bst20051101 · Cited by 201 · cited 2× · see citing works
“Genetic studies have also shown that IDE and NEP gene variations are associated with the clinical symptoms of AD [151, 152].”
BackgroundTriantafilou, M., Gamper, F. G. J., Lepper, P. M., Mouratis, M. A., Schumann, C., Harokopakis, E., Schifferle, R. E., Hajishengallis, G., & Triantafilou, K. (2007) · Cellular Microbiology · doi:10.1111/j.1462-5822.2007.00935.x · Cited by 200 · see citing works
Sheng, J. G., Mrak, R. E., & Griffin, W. S. T. (1994) · Journal of Neuroscience Research · doi:10.1002/jnr.490390406 · Cited by 188 · cited 1× · see citing works
“Tissue levels of S100B correlates with the number of neuritic plaques in the temporal lobe [78, 83] but not in the cerebellum where there is no evidence of neuritic plaques, suggesting a correlation between AD pathology and activated astrocyte.”
BackgroundIn vivo detection of microglial activation in frontotemporal dementia
Cagnin, A., Rossor, M., Sampson, E. L., MacKinnon, T., & Banati, R. B. (2004) · Annals of Neurology · doi:10.1002/ana.20332 · Cited by 187 · cited 1× · see citing works
“Furthermore, studies found activated microglia in vivo (in the brains of AD patients), by using positron emission tomography and 11C-PK111995, which is a marker of peripheral benzodiazepine binding sites that are upregulated on the activated microglia [49, 50].”
BackgroundFrenkel, D., Maron, R., Burt, D. S., & Weiner, H. L. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23241 · Cited by 186 · cited 6× · see citing works
“Protollin might act by stimulating microglial cells both through LPS via TLR4 and through Por B, which makes up 70% of the proteosome protein and activates antigen-presenting cells via TLR2 [143].”
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Sly, L. M., KRZESICKI, R. F., Brashler, J. R., Buhl, A.-L., McKinley, D. D., Carter, D. B., & Chin, J. E. (2001) · Brain Research Bulletin · doi:10.1016/s0361-9230(01)00730-4 · Cited by 174 · cited 1× · see citing works
“In these studies, LPS was given intravenously [155], intracerebroventricularly [156] or intraperitoneally [157].”
MethodBlanc, E. M., Toborek, M. J., Mark, R. J., Hennig, B., & Mattson, M. P. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68051870.x · Cited by 174 · see citing works
Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?
Savarin-Vuaillat, C., & Ransohoff, R. M. (2007) · Neurotherapeutics · doi:10.1016/j.nurt.2007.07.004 · Cited by 173 · see citing works
Hayashi, H., Campenot, R. B., Vance, D. E., & Vance, J. E. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.5471-06.2007 · Cited by 170 · cited 1× · see citing works
“In addition, binding APOE-LPs to LRP initiates the prevention of neuronal apoptosis [102].”
BackgroundCagnin, A. (2001) · Brain · doi:10.1093/brain/124.10.2014 · Cited by 169 · cited 1× · see citing works
“Furthermore, studies found activated microglia in vivo (in the brains of AD patients), by using positron emission tomography and 11C-PK111995, which is a marker of peripheral benzodiazepine binding sites that are upregulated on the activated microglia [49, 50].”
BackgroundModeling microglial activation in Alzheimer's disease with human postmortem microglial cultures
Lue, L. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00311-6 · Cited by 165 · cited 1× · see citing works
“Microglia cultured from rapid autopsies of AD and non-demented patients reveal an increased expression of chemokines such as IL-8, monocyte chemoattractant protein-1 (MCP-1; also known as CCL2) and macrophage inflammatory MIP-1 (CCL3) after experimental exposure to A [70].”
BackgroundGiulian, D., Haverkamp, L. J., Yu, J., Karshin, W. L., Tom, D., Li, J., Kazanskaia, A., Kirkpatrick, J. B., & Roher, A. E. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.45.29719 · Cited by 164 · cited 1× · see citing works
“Soluble A can be directly bound by microglial cell receptors, including the heparan sulphate proteoglycans (HSPGs) [57], insulin receptors [58], proteinase inhibitor (serpin)–enzyme complex receptor (SEC-R) [59] and an accumulation of the receptor for advanced glycation end products (RAGE) [60, 61].”
BackgroundTime-dependent reduction in Aβ levels after intracranial LPS administration in APP transgenic mice
Herber, D., Roth, L. M., Wilson, D., Wilson, N., Mason, J. E., Morgan, D., & Gordon, M. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2004.07.007 · Cited by 164 · cited 1× · see citing works
“However, others studies showed enhanced A clearance through microglial cell activation when LPS was injected intrahippocampally [158, 159] or intracranial [160] to older APP-transgenic mice.”
BackgroundExpression of Scavenger Receptors in Glial Cells
Alarcón, R., Fuenzalida, C., Santibáñez, M., & Rommy von Bernhardi, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414686200 · Cited by 158 · see citing works
Wyss‐Coray, T., Borrow, P., Brooker, M. J., & Mucke, L. (1997) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(97)00049-0 · Cited by 145 · cited 1× · see citing works
“Overexpression of TGF- 1 by the promoter of the GFAP, a specific marker of astrocytes, within the CNS can result in cerebrovascular amyloid and enhance immune cell infiltration from peripherally triggered autoimmune responses [107] (Fig.”
BackgroundGozes, I., Morimoto, B. H., Tiong, J., Fox, A. W., Sutherland, K., Dangoor, D., Holser-Cochav, M., Vered, K., Newton, P. E., Aisen, P. S. S., et al. (2006) · CNS Drug Reviews · doi:10.1111/j.1527-3458.2005.tb00053.x · Cited by 144 · cited 1× · see citing works
“The use of NAP may open up new horizons in research and development of protective compounds to both neurons and the supporting glial cells [166, 167].”
BackgroundMinghetti, L., Carnevale, D., & Simone, R. D. (2007) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152707783399193 · Cited by 144 · see citing works
Butovsky, O., Koronyo‐Hamaoui, M., Kunis, G., Ophir, E., Landa, G., Cohen, H., & Schwartz, M. (2006) · Cited by 144 · see citing works
Mouri, A., Noda, Y., Hara, H., Mizoguchi, H., Tabira, T., & Nabeshima, T. (2007) · The FASEB Journal · doi:10.1096/fj.06-7685com · Cited by 144 · see citing works
Autoantibodies to amyloid-? and Alzheimer's disease
Hyman, B. T., Smith, C. R., Buldyrev, I., Whelan, C. M., Brown, H., Tang, M., & Mayeux, R. P. (2001) · Annals of Neurology · doi:10.1002/ana.1061 · Cited by 144 · see citing works
Eldik, L. J. V., Thompson, W. L., Ranaivo, H. R., Behanna, H. A., & Watterson, D. M. (2007) · International review of neurobiology · doi:10.1016/s0074-7742(07)82015-0 · Cited by 141 · cited 1× · see citing works
“Activated microglia represent the major source of inflammatory factors in the brain in neurodegenerative disorders such as AD [46].”
BackgroundMagnus, T., Chan, A., Grauer, O. M., Toyka, K. V., & Gold, R. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.9.5004 · Cited by 141 · see citing works
Complement Component C1q Modulates the Phagocytosis of Aβ by Microglia
Webster, S. D., Yang, A. J., Margol, L., Garzon-Rodriguez, W., Glabe, C. G., & Tenner, A. J. (2000) · Experimental Neurology · doi:10.1006/exnr.1999.7260 · Cited by 138 · cited 1× · see citing works
“Complement components may modulate the phagocytosis of A by microglia [150].”
BackgroundDivinski, I., Mittelman, L. A., & Gozes, I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403197200 · Cited by 136 · cited 1× · see citing works
“Structure-activity studies identified a short peptide sequence in ADNP, known as a neuronal microtubule-interacting agent (NAP; amino acid sequence NAPVSIPQ), which mimics the neuroprotective activity of the parent protein and crosses the BBB after systemic or intranasal administration and can support the integrity of…”
BackgroundExpression of CD40 in the brain of Alzheimer’s disease and other neurological diseases
Togo, T., Akiyama, H., Kondo, H., Ikeda, K., Kato, M., Iseki, E., & Kosaka, K. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02984-x · Cited by 131 · see citing works
Interleukin-8 receptor B immunoreactivity in brain and neuritic plaques of Alzheimer's disease.
Xia, M., Qin, S., McNamara, M. J., Mackay, C. R., & Hyman, B. T. (1997) · Europe PMC (PubMed Central) · Cited by 131 · see citing works
Hurwitz, A. A., Lyman, W. D., & Herman, J. W. (1995) · Journal of Neuroimmunology · doi:10.1016/0165-5728(95)00011-p · Cited by 130 · see citing works
Kielian, T., Mayes, P. M., & Kielian, M. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00216-3 · Cited by 129 · see citing works
Anti‐Inflammatory Drugs in the Fight against Alzheimer's Diseasea
McGeer, P. L., & McGeer, E. G. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb34421.x · Cited by 123 · cited 1× · see citing works
“Epidemiological studies have documented a reduced prevalence of AD among users of nonsteroidal anti-inflammatory drugs (NSAIDs) [124, 125].”
BackgroundHusemann, J., Loike, J. D., Kodama, T., & Silverstein, S. C. (2001) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(01)00239-9 · Cited by 122 · see citing works
The scavenger receptor MARCO mediates cytoskeleton rearrangements in dendritic cells and microglia
Granucci, F., Petralia, F., Urbano, M., Citterio, S., Tota, F. P. D., Santambrogio, L., & Ricciardi‐Castagnoli, P. (2003) · Blood · doi:10.1182/blood-2002-12-3651 · Cited by 121 · see citing works
Townsend, K. P., Town, T., Mori, T., Lue, L., Shytle, D., Sanberg, P. R., Morgan, D., Fernandez, F., Flavell, R. A., & Tan, J. (2005) · European Journal of Immunology · doi:10.1002/eji.200425585 · Cited by 121 · cited 11× · see citing works
“Suo Z, Tan J, Placzek A, Crawford F, Fang C, Mullan M. Alzheimer’s beta-amyloid peptides induce inflammatory cascade in human vascular cells: the roles of cytokines and CD40.”
BackgroundInfluentialQiao, X., Cummins, D. J., & Paul, S. M. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01666.x · Cited by 119 · cited 1× · see citing works
“In these studies, LPS was given intravenously [155], intracerebroventricularly [156] or intraperitoneally [157].”
MethodChemokines in serum and cerebrospinal fluid of Alzheimer's disease patients
Galimberti, D., Schoonenboom, N. S. M., Scarpini, E. A., & Scheltens, P. (2003) · Annals of Neurology · doi:10.1002/ana.10531 · Cited by 116 · cited 1× · see citing works
“Furthermore, increased levels of MCP-1 and IL-8/CXCL8 can be found in the CSF in the majority of AD patients, therefore chemokines in the CSF may provide a useful diagnosis for AD progression [35].”
BackgroundThe role of intracellular amyloid β in Alzheimer's disease
Li, M. C., Chen, L., Lee, D. H. S., Yu, L., & Zhang, Y. (2007) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2007.08.002 · Cited by 116 · see citing works
Suo, Z., Tan, J., Placzek, A., Crawford, F., Fang, C., & Mullan, M. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00780-x · Cited by 116 · see citing works
Husemann, J., & Silverstein, S. C. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64030-8 · Cited by 115 · see citing works
Binding Sites of Amyloid β-Peptide in Cell Plasma Membrane and Implications for Alzheimers Disease
Verdier, Y., & Penke, B. (2004) · Current Protein and Peptide Science · doi:10.2174/1389203043486937 · Cited by 114 · cited 1× · see citing works
“Targeting SRs can mediate the activation of glial cells towards A clearance [147].”
BackgroundCerebral amyloid angiopathy: Pathogenesis and effects on the ageing and Alzheimer brain
Weller, R. O., & Nicoll, J. A. R. (2003) · Neurological Research · doi:10.1179/016164103101202057 · Cited by 112 · cited 2× · see citing works
“The deposits cause intraparenchymal and subarachnoid bleeding, which leads to haemorrhage, stroke with hemosiderin deposits, multiple infarcts and cognitive impairment [109] (Fig.”
BackgroundAlzheimer's disease and soluble Aβ
Wısnıewskı, T., Ghiso, J. A., & Frangione, B. (1994) · Neurobiology of Aging · doi:10.1016/0197-4580(94)90105-8 · Cited by 111 · see citing works
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Evidence of a Role for Lactadherin in Alzheimer's Disease
Boddaert, J., Kinugawa, K., Lambert, J., Boukhtouche, F., Zoll, J., Merval, R., Blanc‐Brude, O., Mann, D. M. A., Berr, C., Vilar, J., et al. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.060664 · Cited by 106 · cited 2× · see citing works
“One study found that there is less lactadherin found in the brains of AD patients [149].”
BackgroundMicroglial transplantation increases amyloid‐β clearance in Alzheimer model rats
Takata, K., Kitamura, Y., Yanagisawa, D., Morikawa, S., Morita, M., Inubushi, T., Tsuchiya, D., Chishiro, S., Saeki, M., Taniguchi, T., et al. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.01.009 · Cited by 106 · see citing works
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“Thereby activation of the complement system can lead to increased phagocytosis of A by microglial cells [30].”
BackgroundIribarren, P., Zhou, Y., Hu, J., Le, Y., & Wang, J. M. (2005) · Immunologic Research · doi:10.1385/ir:31:3:165 · Cited by 104 · see citing works
Dolev, I., & Michaelson, D. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404458101 · Cited by 102 · see citing works
Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer's disease
Quinn, J. (2003) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(03)00037-7 · Cited by 102 · cited 1× · see citing works
“However, others studies showed enhanced A clearance through microglial cell activation when LPS was injected intrahippocampally [158, 159] or intracranial [160] to older APP-transgenic mice.”
BackgroundHara, H., Monsonego, A., Yuasa, K., Adachi, K., Xiao, X., Takeda, S., Takahashi, K., Weiner, H. L., & Tabira, T. (2004) · Journal of Alzheimer s Disease · doi:10.3233/jad-2004-6504 · Cited by 90 · see citing works
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“Soluble A can be directly bound by microglial cell receptors, including the heparan sulphate proteoglycans (HSPGs) [57], insulin receptors [58], proteinase inhibitor (serpin)–enzyme complex receptor (SEC-R) [59] and an accumulation of the receptor for advanced glycation end products (RAGE) [60, 61].”
BackgroundGenetic factors in Alzheimer's disease: A review of recent advances
Levy‐Lahad, E., & Bird, T. D. (1996) · Annals of Neurology · doi:10.1002/ana.410400604 · Cited by 86 · cited 2× · see citing works
“The protective effect was greater for ApoE3 than for ApoE4, the expression of which is a risk factor for AD [103].”
BackgroundFrenkel, D., Dewachter, I., LEUVEN, F. V., & Solomon, B. (2003) · Vaccine · doi:10.1016/s0264-410x(02)00609-6 · Cited by 85 · see citing works
Self-citationTGF-β Pathway as a Potential Target in Neurodegeneration and Alzheimers
Wyss-Coray, T. (2006) · Current Alzheimer Research · doi:10.2174/156720506777632916 · Cited by 85 · cited 2× · see citing works
“TGF- 1 is a multi-functional cytokine that is a major regulator of the immune response and has profound affects on vasculogenesis, angiogenesis and the maintenance of vessel wall integrity [43].”
BackgroundHuman antibodies reactive with beta-amyloid protein in Alzheimer's disease.
Gaskin, F., Finley, J., Fang, Q., Xu, S., & Fu, S. M. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.177.4.1181 · Cited by 82 · cited 14× · see citing works
“Glial cells secrete the LRP ligand, ApoE-containing lipoproteins (ApoE-LPs) [101], which have an important role in lipid homeostasis in the CNS. Glia-derived APOELPs also promote synaptogenesis and stimulate axon growth of CNS neurons [101].”
BackgroundInfluentialNon-steroidal Anti-inflammatory Drugs and Cyclooxygenase in Alzheimer s Disease
Hoozemans, J. J. M., Veerhuis, R., Rozemüller, A. J. M., & Eikelenboom, P. (2003) · Current Drug Targets · doi:10.2174/1389450033490902 · Cited by 81 · cited 2× · see citing works
“The main known target of NSAIDs are the cyclooxygenase (COX) enzymes [125].”
BackgroundStructure-function studies of the receptors for complement C1q
McGreal, E. P., & Gasque, P. (2002) · Biochemical Society Transactions · doi:10.1042/bst0301010 · Cited by 80 · see citing works
Shibata, N., Ohnuma, T., Takahashi, T., Baba, H., Ishizuka, T., Ohtsuka, M., Ueki, A., Nagao, M., & Arai, H. (2002) · American Journal of Medical Genetics · doi:10.1002/ajmg.10417 · Cited by 80 · cited 5× · see citing works
“Isolated microglia from postmortem AD and control (non-demented) patients’ brain tissue exhibit pro-inflammatory cytokine expression profiles, in the form of a significantly increased expression of IL-1 , TNF- , IL-6 and IL-12, following an exposure to A peptides.”
BackgroundInfluentialTNF alpha affects the expression of GFAP and S100B: implications for Alzheimer’s disease
Edwards, M. M., & Robinson, S. R. (2006) · Journal of Neural Transmission · doi:10.1007/s00702-006-0479-5 · Cited by 79 · cited 1× · see citing works
“Astrocyte activity is marked by hypertrophy [79], resulting in an expression of proteins such as glial fibrillary acidic protein (GFAP), S100B [78, 80], adhesion molecules and antigen presenting capabilities, including MHC antigens [81, 82].”
BackgroundCui, Y., Le, Y., Yazawa, H., Gong, W., & Wang, J. M. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.72.4.628 · Cited by 78 · see citing works
The femtomolar-acting NAP interacts with microtubules: Novel aspects of astrocyte protection
Gozes, I., & Divinski, I. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2004-6s605 · Cited by 77 · cited 1× · see citing works
“The use of NAP may open up new horizons in research and development of protective compounds to both neurons and the supporting glial cells [166, 167].”
BackgroundMechanisms of cell death in Alzheimer disease — immunopathology
McGeer, P. L., & McGeer, E. G. (1998) · Journal of neural transmission. Supplementum · doi:10.1007/978-3-7091-7508-8_15 · Cited by 75 · cited 1× · see citing works
“Journal compilation © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd provide a specific mechanism for recruiting reactive glial cells to the sites of the A plaque and lead to inflammatory events, neuronal dysfunction and degeneration through production of pro-inflammatory cytokines and ox…”
BackgroundAstrocytes and intracerebral immune responses
Frohman, E. M., van den Noort, S., & Gupta, S. (1989) · Journal of Clinical Immunology · doi:10.1007/bf00917121 · Cited by 72 · cited 1× · see citing works
“Astrocyte activity is marked by hypertrophy [79], resulting in an expression of proteins such as glial fibrillary acidic protein (GFAP), S100B [78, 80], adhesion molecules and antigen presenting capabilities, including MHC antigens [81, 82].”
BackgroundMicroglial interaction with β‐amyloid: Implications for the pathogenesis of Alzheimer's disease
Bamberger, M. E., & Landreth, G. E. (2001) · Microscopy Research and Technique · doi:10.1002/jemt.1121 · Cited by 71 · see citing works
Immunohistochemical and Ultrastructural Studies
Kikuchi, A., Akiyama, M., Hanyaku, H., Shimizu, H., Naka, W., & Nishikawa, T. (1993) · American Journal of Dermatopathology · doi:10.1097/00000372-199302000-00003 · Cited by 71 · see citing works
Fas Ligand (CD95L) Protects Neurons Against Perforin- Mediated T Lymphocyte Cytotoxicity
Medana, I. M., Li, Z., Flügel, A., Tschopp, J., Wekerle, H., & Neumann, H. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.2.674 · Cited by 71 · see citing works
The role of apolipoprotein E in lipid metabolism in the central nervous system
Han, X.-L. (2004) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-004-4009-z · Cited by 70 · cited 2× · see citing works
“Glial cells secrete the LRP ligand, ApoE-containing lipoproteins (ApoE-LPs) [101], which have an important role in lipid homeostasis in the CNS.”
BackgroundNeuroglial networks: Neurons and glia talk to each other
Haydon, P. G. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00708-9 · Cited by 66 · cited 1× · see citing works
“Astrocytes are the most abundant cells in the CNS and play an important role in the homeostasis and maintenance of the brain [74, 75].”
BackgroundLaminin inhibits amyloid-β-peptide fibrillation
Bronfman, F. C., Garrido, J., Alvarez, A. R., Morgan, C., & Inestrosa, N. C. (1996) · Neuroscience Letters · doi:10.1016/s0304-3940(96)13147-5 · Cited by 62 · see citing works
Inflammation in the nervous system — Physiological and pathophysiological aspects
Schultzberg, M., Lindberg, C., Aronsson, Å. F., Hjorth, E., Spulber, S. D., & Oprica, M. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.05.050 · Cited by 61 · cited 1× · see citing works
“Pro-inflammatory cytokines, such as interleukin1 (IL-1 / [36, 37], tumour necrosis factor- (TNF- ) [38] and IL-6 [39], may play an important role in AD pathology and lead to an increased production of inducible nitric oxide synthase (iNOS), neuronal stress and further neuronal dysfunction and death [40].”
BackgroundStrazielle, N., Ghersi‐Egea, J., Ghiso, J. A., Dehouck, M., Frangione, B., Patlak, C. S., Fenstermacher, J. D., & Gorevic, P. D. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.1.29 · Cited by 59 · cited 1× · see citing works
“A increases endothelial monolayer permeability [111, 112], stimulates secretion of inflammatory cytokines [113] and up-regulates vascular cell adhesion molecules (Fig.”
BackgroundProtollin™: a novel adjuvant for intranasal vaccines
Jones, T., Cyr, S. L., Allard, F., Bellerose, N., Lowell, G. H., & Burt, D. S. (2004) · Vaccine · doi:10.1016/j.vaccine.2004.03.035 · Cited by 52 · cited 1× · see citing works
“Furthermore, nasal administration of a proteosome-based adjuvant (Protollin) [161], composed of purified outer membrane proteins of Neisseria meningitides and LPS, also reduces A in”
BackgroundGliosis in human brain: relationship to size but not other properties of astrocytes
da Cunha, A., Jefferson, J. J., Tyor, W. R., Glass, J. D., Jannotta, F. S., & Vitković, L. (1993) · Brain Research · doi:10.1016/0006-8993(93)90415-j · Cited by 51 · cited 1× · see citing works
“Astrocyte activity is marked by hypertrophy [79], resulting in an expression of proteins such as glial fibrillary acidic protein (GFAP), S100B [78, 80], adhesion molecules and antigen presenting capabilities, including MHC antigens [81, 82].”
BackgroundSofroniew, M. V., Bush, T. G., Blumauer, N., Kruger, L., Mucke, L., & Johnson, M. H. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01639-x · Cited by 48 · cited 1× · see citing works
“Astrocytes are the most abundant cells in the CNS and play an important role in the homeostasis and maintenance of the brain [74, 75].”
BackgroundPossible role of scavenger receptor SRCL in the clearance of amyloid‐βin Alzheimer's disease
Nakamura, K. D., Ohya, W., Funakoshi, H., Sakaguchi, G., Kato, A., Takeda, M., Kudo, T., & Nakamura, T. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.20992 · Cited by 46 · cited 1× · see citing works
“The presence of a large number of SRCL together with A double-positive particles in the intracellular compartments of reactive astrocytes and vascular or perivascular cells in APP mice suggests a role for SRCL in A clearance [148].”
BackgroundYamada, T., Miyazaki, K., Koshikawa, N., Takahashi, M., Akatsu, H., & Yamamoto, T. (1995) · Acta Neuropathologica · doi:10.1007/bf00309334 · Cited by 45 · cited 1× · see citing works
“Glial cells can also degrade A by releasing other A -degrading enzymes, such as metalloproteases, and gelatinase A [153, 154].”
BackgroundQuintana, F. J., Zaltzman, R., Fernández-Montesinos, R., HERRERA, J. L., Gozes, I., Cohen, I. R., & Pozo, D. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1317.069 · Cited by 43 · cited 3× · see citing works
“These include TNF- [84], IL-6 [85] and IL-12 [85].”
Background(2007) · PubMed · Cited by 43 · see citing works
Astrocyte-Apolipoprotein E Associations in Senile Plaques in Alzheimer Disease and Vascular Lesions
Shao, Y., Gearing, M., & Mirra, S. S. (1997) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199704000-00006 · Cited by 41 · cited 1× · see citing works
“In an AD patient’s brain, reactive astrocytes are integral components of neuritic plaques [77, 78].”
BackgroundBsibsi, M., Bajramovic, J. J., van Duijvenvoorden, E., Persoon-Deen, C., Ravid, R., van Noort, J. M., & Vogt, M. H. J. (2007) · Glia · doi:10.1002/glia.20473 · Cited by 40 · cited 6× · see citing works
“Isolated microglia from postmortem AD and control (non-demented) patients’ brain tissue exhibit pro-inflammatory cytokine expression profiles, in the form of a significantly increased expression of IL-1 , TNF- , IL-6 and IL-12, following an exposure to A peptides.”
InfluentialCcr2 Deficiency Impairs Microglial Accumulation and Accelerates Progression of Alzheimer's Disease
Khoury, J. B. E., Graham, M., Hickman, S. E., Geula, C., Means, T. K., & Luster, A. D. (2007) · Clinical Immunology · doi:10.1016/j.clim.2007.03.030 · Cited by 38 · see citing works
Oprica, M., Hjorth, E., Spulber, S. D., Popescu, B. O., Ankarcrona, M., Winblad, B. G., & Schultzberg, M. (2007) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2007.00074.x · Cited by 37 · cited 1× · see citing works
“Pro-inflammatory cytokines, such as interleukin1 (IL-1 / [36, 37], tumour necrosis factor- (TNF- ) [38] and IL-6 [39], may play an important role in AD pathology and lead to an increased production of inducible nitric oxide synthase (iNOS), neuronal stress and further neuronal dysfunction and death [40].”
BackgroundGasque, P., Jones, J. G., Singhrao, S. K., & Morgan, B. P. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.4.451 · Cited by 36 · see citing works
Effects of apoE isoforms on beta-amyloid-induced matrix metalloproteinase-9 in rat astrocytes
Guo, S., Wang, S., Kim, W. J., Lee, S.-R., Frosch, M. P., Bacskai, B. J., Greenberg, S. M., & Lo, E. H. (2006) · Brain Research · doi:10.1016/j.brainres.2006.06.041 · Cited by 34 · cited 1× · see citing works
“Furthermore, high expression of APOE4 in astrocytes can reduce their response to A deposits [94, 95].”
BackgroundNovel strategies for Alzheimer's disease treatment
Spencer, B. J., Rockenstein, E. M., Crews, L. A., Marr, R. A., & Masliah, E. (2007) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.7.12.1853 · Cited by 31 · cited 1× · see citing works
“Adult hippocampal neurogenesis, the process that creates neurons, dramatically decreases with increasing age and it has been proposed that this decline may contribute to age-related memory deficits, such as in AD [168, 169].”
BackgroundComplement activation in acquired and hereditary amyloid neuropathy
Hafer‐Macko, C. E., Dyck, P. J. B., & Koski, C. L. (2000) · Journal of the Peripheral Nervous System · doi:10.1046/j.1529-8027.2000.00018.x · Cited by 28 · cited 1× · see citing works
“Complement component 1q (C1q) has been shown to colocalize with most of the amyloid deposits in brains of AD patients [23–25] and triggers a complement cascade, including the formation of the membrane attack complex (MAC), C5b–C9 [26].”
BackgroundHLA class I, II & III genes in confirmed late-onset Alzheimer's disease
Lehmann, D. J. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00180-9 · Cited by 27 · see citing works
Antibody-mediated immunotherapy for Alzheimer's disease.
Solomon, B. (2007) · PubMed · Cited by 27 · see citing works
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“Yang J, Aschner M. Developmental aspects of blood-brain barrier (BBB) and rat brain endothelial (RBE4) cells as in vitro model for studies on chlorpyrifos transport.”
BackgroundInfluentialMicroglial activation by uptake of fDNA via a scavenger receptor
Li, Y., Liu, L., Liu, D., Woodward, S., Barger, S. W., Mrak, R. E., & Griffin, W. S. T. (2003) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2003.10.043 · Cited by 24 · cited 2× · see citing works
“An accumulation of damaged neuronal DNA fragments can be potent promoters of microglial activation in AD [51].”
BackgroundVery early‐onset familial Alzheimer's disease: a novel presenilin 1 mutation
Goldman, J. S., Reed, B., Gearhart, R., Kramer, J. H., & Miller, B. L. (2002) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.657 · Cited by 24 · cited 1× · see citing works
“Most cases of AD are sporadic, while less than 5% of cases are early onset familial Alzheimer’s disease (EOFAD; age at onset < 65 years) with an autosomal dominant pattern of inheritance [4].”
BackgroundThe influence of the peptide NAP on Mac-1-deficient mice following closed head injury
Zaltzman, R., Alexandrovich, A. G., Trembovler, V., Shohami, E., & Gozes, I. (2005) · Peptides · doi:10.1016/j.peptides.2005.03.014 · Cited by 22 · cited 1× · see citing works
“Structure-activity studies identified a short peptide sequence in ADNP, known as a neuronal microtubule-interacting agent (NAP; amino acid sequence NAPVSIPQ), which mimics the neuroprotective activity of the parent protein and crosses the BBB after systemic or intranasal administration and can support the integrity of…”
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Beta-amyloid-based immunotherapy as a treatment of Alzheimer's disease
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Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease
Turner, M. D., Nedjai, B., Hurst, T. P., & Pennington, D. J. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.05.014 · Cited by 2,186 · see citing works
“However there is also evidence that microglia can have neurotoxic effects in the brain [212], likely via the release of potent pro-inflammatory molecules [213] and other immunomodulatory molecules which lead to the recruitment of monocytes and lymphocytes through the blood-brain barrier (BBB) [214,215].”
BackgroundSpreading of pathology in neurodegenerative diseases: a focus on human studies
Brettschneider, J., Tredici, K. D., Lee, V. M.-Y., & Trojanowski, J. Q. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3887 · Cited by 790 · see citing works
Interaction of Microglia and Astrocytes in the Neurovascular Unit
Liu, L., Liu, J., Bao, J.-S., Bai, Q.-Q., & Wang, G. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01024 · Cited by 591 · see citing works
“Microglia, scattered throughout the brain, wander more observantly and detect modifications of their environment as sentinels (42, 53).”
BackgroundMicroglia-Astrocyte Crosstalk: An Intimate Molecular Conversation
Jha, M. K., Jo, M., Kim, J.-H., & Suk, K. (2019) · The Neuroscientist · doi:10.1177/1073858418783959 · Cited by 579 · see citing works
González-Reyes, R. E., Nava-Mesa, M. O., Vargas-Sánchez, K., Ariza-Salamanca, D. F., & Mora-Muñoz, L. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00427 · Cited by 525 · see citing works
“RAGE, Astrocytes, and Amyloid Beta Amyloid beta has been reported to interact with numerous cellular receptors and astrocytes express a large amount of them, including TLRs, scavenger receptors, glycoprotein receptors, lipoprotein receptors, RAGE, acetylcholine receptors, complement and chemokine receptors, T-cell rec…”
BackgroundNOX Enzymes in the Central Nervous System: From Signaling to Disease
Sorce, S., & Krause, K. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2578 · Cited by 472 · see citing works
The neuroinflammatory hypothesis of delirium
Cerejeira, J., Firmino, H., Vaz‐Serra, A., & Mukaetova‐Ladinska, E. B. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0674-1 · Cited by 482 · see citing works
“However, reactivity of microglia and astrocytes against Ab can promote or exacerbate the neuropathological changes of AD [43, 97].”
BackgroundThe role of astroglia in neuroprotection
Bélanger, M., & Magistretti, P. J. (2009) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2009.11.3/mbelanger · Cited by 396 · see citing works
Role of Redox Signaling in Neuroinflammation and Neurodegenerative Diseases
Hsieh, H., & Yang, C. (2013) · BioMed Research International · doi:10.1155/2013/484613 · Cited by 370 · see citing works
Wang, G., Dinkins, M. B., He, Q., Zhu, G., Poirier, C., Campbell, A., Mayer‐Pröschel, M., & Bieberich, E. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.340513 · Cited by 356 · see citing works
Astrocytes: Role and Functions in Brain Pathologies
Siracusa, R., Fusco, R., & Cuzzocrea, S. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01114 · Cited by 342 · see citing works
Microglia–blood vessel interactions: a double-edged sword in brain pathologies
Dudvarski Stankovic, N., Teodorczyk, M., Ploen, R., Zipp, F., & Schmidt, M. H. H. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1524-y · Cited by 301 · see citing works
Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment
Harry, G. J., & Kraft, A. D. (2008) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.4.10.1265 · Cited by 292 · see citing works
“For additional reading on the issue of heterogeneity of microglia responses the reader is directed to the following references [1,2,3,4,5].”
BackgroundRecent advances in our understanding of neurodegeneration
Jellinger, K. A. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0240-y · Cited by 274 · see citing works
“pro-inflammatory agent inducing the activation of glia and many of the inflammatory components (Bonifati and Kishore 2007; Farfara et al. 2008; Sondag et al. 2009).”
BackgroundEvidence That Aging And Amyloid Promote Microglial Cell Senescence
Flanary, B. E., Sammons, N. W., Nguyen, C., Walker, D., & Streit, W. J. (2007) · Rejuvenation Research · doi:10.1089/rej.2006.9096 · Cited by 272 · see citing works
Microglia and neuroprotection: From in vitro studies to therapeutic applications
Polazzi, E., & Monti, B. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.06.009 · Cited by 260 · see citing works
Carroll, J. C., Iba, M., Bangasser, D. A., Valentino, R. J., James, M. J., Brunden, K. R., Lee, V. M. ‐., & Trojanowski, J. Q. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3836-11.2011 · Cited by 256 · see citing works
“The link between AD, A , and activation of the brain immune response, with the release of proinflammatory cytokines and chemokines, is well documented (Benzing et al., 1999; Farfara et al., 2008).”
BackgroundWNT signaling in activated microglia is proinflammatory
Halleskog, C., Mulder, J., Dahlström, J., Mackie, K., Hortobágyi, T., Tanila, H., Puli, L., Färber, K., Harkany, T., & Schulte, G. (2010) · Glia · doi:10.1002/glia.21081 · Cited by 216 · see citing works
“Proinflammatory cytokine release is a hallmark of activated microglia and contributes to chronic neuroinflammation (Farfara et al., 2008).”
BackgroundTamboli, I. Y., Barth, E., Christian, L., Siepmann, M., Kumar, S., Singh, S., Tolksdorf, K., Heneka, M. T., Lütjohann, D., Wunderlich, P., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.149468 · Cited by 219 · see citing works
Kiyota, T., Dixie, K. L. I., Swan, R. J., Jacobsen, M. T., Andrews, S. J., & Ikezu, T. (2011) · Gene Therapy · doi:10.1038/gt.2011.126 · Cited by 216 · see citing works
CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration
Koper‐Lenkiewicz, O. M., Kamińska, J., Sawicki, K., & Kemona, H. (2018) · Advances in Clinical and Experimental Medicine · doi:10.17219/acem/68846 · Cited by 217 · see citing works
“(1-42) in association with neurofibrillary tangle (NFT) formation in the brain, which leads to irreversible neuronal damage (severe reduction in the brain weight of more than 35% post-mortem AD cases was noted).”
BackgroundKiyota, T., Okuyama, S., Swan, R. J., Jacobsen, M. T., Gendelman, H. E., & Ikezu, T. (2010) · The FASEB Journal · doi:10.1096/fj.10-155317 · Cited by 212 · see citing works
“Although A triggers the accumulation of astrocytes and microglia that produce proinflammatory cytokines and chemokines causing chronic neuroinflammation (10), glatiramer acetate (GA)-treated animals develop Th2 cells, which suppress the inflammatory response and secrete anti-inflammatory cytokines such as IL-4 (11, 12…”
BackgroundAstrocyte–neuron interactions in neurological disorders
Ricci, G., Volpi, L., Pasquali, L., Petrozzi, L., & Siciliano, G. (2009) · Journal of Biological Physics · doi:10.1007/s10867-009-9157-9 · Cited by 205 · see citing works
“distribution of RAGE and LRP-1 in human hippocampus, compared with age-matched controls [140, 141].”
BackgroundShared Mechanisms of Neurodegeneration in Alzheimer’s Disease and Parkinson’s Disease
Xie, A., Gao, J., Xu, L., & Meng, D.-M. (2014) · BioMed Research International · doi:10.1155/2014/648740 · Cited by 196 · see citing works
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Serum levels of S100B and NSE proteins in Alzheimer's disease patients
Chaves, M. L. F., Camozzato, A. L., Ferreira, E. D., Piazenski, I., Kochhann, R., Dall'Igna, O. P. P., Mazzini, G. S., Souza, D. O., & Portela, L. V. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-6 · Cited by 189 · see citing works
“Once activated, these cells increase the expression of substances that can participate in the excitotoxicity and inflammatory processes that occur during the evolution of AD [37].”
BackgroundScalabrino, G. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.04.004 · Cited by 177 · see citing works
Heart failure and Alzheimer′s disease
Čermáková, P., Eriksdotter, M., Lund, L. H., Winblad, B. G., Religa, P., & Religa, D. (2014) · Journal of Internal Medicine · doi:10.1111/joim.12287 · Cited by 166 · see citing works
Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat
Cao, T., Thomas, T. C., Ziebell, J. M., Pauly, J. R., & Lifshitz, J. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.08.058 · Cited by 160 · see citing works
Increased Matrix Metalloproteinase 9 Activity in Mild Cognitive Impairment
Bruno, M. A., Mufson, E. J., Wuu, J., & Cuello, A. C. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181c22569 · Cited by 163 · see citing works
“tumor necrosis factor, interleukin-1A, and interleukin-6 [65, 66]) that also regulate MMP-9 expression (13).”
In vivo imaging of synaptic function in the central nervous system
Nikolaus, S., Antke, C., & Müller, H. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.06.008 · Cited by 153 · see citing works
Noda, M., Doi, Y., Liang, J., Kawanokuchi, J., Sonobe, Y., Takeuchi, H., Mizuno, T., & Suzumura, A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.169839 · Cited by 144 · see citing works
Wan, J., Fu, A. K. Y., Ip, F. C. F., Ng, H., Hugon, J., Page, G., Wang, J. H.-C., Lai, K., Wu, Z., & Ip, N. Y. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0519-10.2010 · Cited by 143 · see citing works
“Indeed, cytokines released from glia have been suggested to cause neuronal death, although the mechanisms remain unclear (Mrak and Griffin, 2005; Farfara et al., 2008).”
BackgroundPan, Y., & Nicolazzo, J. A. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.04.009 · Cited by 131 · see citing works
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Lee, C., Park, G. H., Kim, C., & Jang, J. (2011) · Food and Chemical Toxicology · doi:10.1016/j.fct.2011.03.005 · Cited by 130 · see citing works
Primary Cerebral Blood Flow Deficiency and Alzheimer's Disease: Shadows and Lights
Mazza, M., Marano, G., Traversi, G., Bria, P., & Mazza, S. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-090700 · Cited by 129 · see citing works
Role of docosahexaenoic acid in the modulation of glial cells in Alzheimer’s disease
Heras-Sandoval, D., Pedraza-Chaverri, J., & Pérez-Rojas, J. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0525-7 · Cited by 104 · see citing works
“subsequent release pro-inflammatory molecules in the AD brain [52, 53].”
BackgroundInfluentialJia, S., Zheng, L., Gao, Z., An, J., Wu, X., Li, X., Dai, X., Zheng, Q., & Sun, Y. (2015) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2015.11.011 · Cited by 121 · see citing works
Trudler, D., Farfara, D., & Frenkel, D. (2010) · Mediators of Inflammation · doi:10.1155/2010/497987 · Cited by 117 · see citing works
“While the role of inflammation in disease progression in AD is not fully understood, an increased amount of findings suggest that Aβ deposition and NFT activate a potentially pathological innate immune response in the disease [81].”
BackgroundSelf-citationJesse, S., Steinacker, P., Cepek, L., Arnim, C. A. F. V., Tumani, H., Lehnert, S., Kretzschmar, H. A., Baier, M., & Otto, M. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1075 · Cited by 110 · see citing works
“Mediators, released by astrocytes, activate neighboringcells and amplify the local, initial immune response further, modify BBB permeability, and attract immune cells from the blood circulation into the neural tissue, thus supporting an adaptive immune response [63].”
Nicotinic Attenuation of Central Nervous System Inflammation and Autoimmunity
Shi, F., Piao, W.-H., Kuo, Y., Campagnolo, D. I., Vollmer, T. L., & Lukas, R. J. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.182.3.1730 · Cited by 106 · see citing works
Barreto, G. E., Santos‐Galindo, M., Diz-Chaves, Y., Pernía, O., Carrero, P., Azcoitia, Í., & García‐Segura, L. M. (2009) · Endocrinology · doi:10.1210/en.2009-0352 · Cited by 103 · see citing works
“In addition, the antigliotic effect of estradiol and SERMs on aged females may be particularly relevant for chronic neurodegenerative diseases associated with aging, in which it is suspected that a dysfunction of glial cells may contribute to increased neural damage (43, 44).”
BackgroundFreund‐Levi, Y., Hjorth, E., Lindberg, C., Cederholm, T., Irving, G. F., Vedin, I., Palmblad, J. E. W., Wahlund, L., Schultzberg, M., Basun, H., et al. (2009) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000218081 · Cited by 100 · see citing works
“Microglia release cytokines, e.g. interleukin (IL)-1β, IL-6, and tumour necrosis factor-α (TNF-α), which may lead to neuronal dysfunction [”
BackgroundEmerging roles of microglial activation and non-motor symptoms in Parkinson's disease
Doorn, K. J., Lucassen, P. J., Boddeke, H. W. G. M., Prins, M., Berendse, H. W., Drukarch, B., & van Dam, A. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.06.005 · Cited by 97 · see citing works
Azevedo, E. P., Guimarães-Costa, A. B., Torezani, G. S., Braga, C. A. C. A., Palhano, F. L., Kelly, J. W., Saraiva, E. M., & Foguel, D. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.369942 · Cited by 97 · see citing works
“It has been shown that amyloid fibrils can induce an inflammatory response in which cytokines are secreted by macrophages and glial cells (6, 7).”
BackgroundBeckers, L., Ory, D., Geric, I., Declercq, L., Koole, M. J. B., Kassiou, M., Bormans, G. M., & Baes, M. I. (2017) · Molecular Imaging and Biology · doi:10.1007/s11307-017-1099-1 · Cited by 93 · see citing works
“Although microglia with either a pro- or antiinflammatory signature can occur in defined pathological conditions [22], it is now accepted that microglia in vivomostly adopt mixed pro- and anti-inflammatory phenotypes in neurological disorders [17, 34, 35].”
BackgroundLin, P.-Y., Cheng, C., Satyanarayanan, S. K., Chiu, L., Chien, Y.-C., Chuu, C., Lan, T., & Su, K. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.10.014 · Cited by 93 · see citing works
Aβ Internalization by Neurons and Glia
Mohamed, A., & Chaves, E. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/127984 · Cited by 91 · see citing works
The Potential Role of Chemokines in Alzheimer’s Disease Pathogenesis
Azizi, G., Hossein‐Khannazer, N., & Mirshafiey, A. (2014) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317513518651 · Cited by 89 · see citing works
Walker, L. C. (2020) · Free Neuropathology · doi:10.17879/freeneuropathology-2020-3025 · Cited by 95 · see citing works
Alzheimer's Disease: Evidence for the Expression of Interleukin-33 and Its Receptor ST2 in the Brain
Xiong, Z., Thangavel, R., Kempuraj, D., Yang, E., Zaheer, S. A., & Zaheer, A. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-132081 · Cited by 84 · see citing works
“Alzheimer’s disease (AD) is the most common form of dementia among the elderly, affecting 5 million Americans and more than 35 million individuals worldwide [1, 2].”
Aquaporin-4 mediates astrocyte response to β-amyloid
Yang, W., Wu, Q., Chan, Y., Gao, J., Xiao, M., Gu, M., Ding, J., & Hu, G. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.02.002 · Cited by 83 · see citing works
Gresa‐Arribas, N., Serratosa, J., Saura, J., & Solà, C. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06952.x · Cited by 81 · see citing works
“The presence of inflammation and the involvement of reactive glial cells has been described in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis (Jack et al. 2005; Sargsyan et al. 2005; Lucas et al. 2006; Lobsiger and Cleveland 2007; Whitton 2007; Farf…”
BackgroundLü, P., Mamiya, T., Lu, L., Mouri, A., Niwa, M., Hiramatsu, M., Zou, L., Nagai, T., Ikejima, T., & Nabeshima, T. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.155069 · Cited by 80 · see citing works
“The deposition of A is invariably associated with oxidative stress and inflammatory response, which may contribute to neuronal dysfunction or death (Butterfield et al., 2007; Farfara et al., 2008).”
BackgroundKempuraj, D., Khan, M. M., Thangavel, R., Xiong, Z., Yang, E., & Zaheer, A. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9439-7 · Cited by 79 · see citing works
“High level of CCL2 was found in the cerebrospinal fluid (CSF) of AD patients (Farfara et al. 2008) and MS patients, and EAE (Conductier et al. 2010).”
Ben-Menachem-Zidon, O., Ben-Menahem, Y., Ben-Hur, T., & Yirmiya, R. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.208 · Cited by 78 · see citing works
“Microglia, which are responsible for most (but not all) production of brain IL-1, have key roles in the formation and degradation of plaques in AD (Farfara et al, 2008; Lynch, 2009; Weitz and Town, 2012), and may be also involved in cognitive functioning and neurogenesis (Blank and Prinz, 2013;…”
BackgroundInhibition of cholinesterase by essential oil from food plant
Chaiyana, W., & Okonogi, S. (2012) · Phytomedicine · doi:10.1016/j.phymed.2012.03.010 · Cited by 77 · see citing works
Siglec receptors and hiding plaques in Alzheimer's disease
Salminen, A., & Kaarniranta, K. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0472-1 · Cited by 73 · see citing works
“Neuritic plaques, also called senile plaques, are large extracellular deposits of β-amyloid fibrils which are associated with a plethora of other material in conjunction with microglial and astrocytic cells [1, 2 ]. Neuritic plaques with their dense core of insoluble material are located in specific brain regions, e.g…”
BackgroundClough, E., Inigo, J., Chandra, D., Chaves, L., Reynolds, J. L., Aalinkeel, R., Schwartz, S. A., Khmaladze, A., & Mahajan, S. D. (2021) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-021-10015-6 · Cited by 75 · see citing works
Imbimbo, B. P., Giardino, L., Sivilia, S., Giuliani, A., Gusciglio, M., Pietrini, V., Giudice, E. D., D’Arrigo, A., Leon, A., Villetti, G., et al. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1366 · Cited by 74 · see citing works
“It has been suggested that reactive astrocytes encompasses both beneficial and detrimental reactions [49].”
Role of astroglia in the neuroplastic and neuroprotective actions of estradiol
Azcoitia, Í., Santos‐Galindo, M., Arévalo, M., & García‐Segura, L. M. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07516.x · Cited by 72 · see citing works
“However, the antigliotic effect of estradiol may be relevant for chronic neurodegenerative diseases, where it is suspected that a dysfunction of glial cells may contribute to increased neural damage (Mrak & Griffin, 2005; Farfara et al., 2008).”
BackgroundAzizi, G., & Mirshafiey, A. (2012) · Immunopharmacology and Immunotoxicology · doi:10.3109/08923973.2012.705292 · Cited by 72 · see citing works
“Dysfunction of glial cells may promote neurodegeneration and, eventually the retraction of neuronal synapses, which leads to cognitive deficits.((19)) The involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD is becoming increasingly recognized.”
BackgroundWNT5A Signaling Contributes to Aβ-Induced Neuroinflammation and Neurotoxicity
Li, B., Zhong, L., Yang, X., Andersson, T., Huang, M., & Tang, S.-J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022920 · Cited by 81 · see citing works
“AD neuroinflammation is likely triggered by Ab-mediated activation of microglia and astrocytes [3,4, 12,13,14].”
BackgroundOh, J., Cho, W.-H., Barcelon, E. E., Kim, K. H., Hong, J., & Lee, S. J. (2022) · Scientific Reports · doi:10.1038/s41598-022-09410-7 · Cited by 72 · see citing works
Involvement of TRPV4 channels in Aβ40-induced hippocampal cell death and astrocytic Ca2+ signalling
Bai, J., & Lipski, J. (2014) · NeuroToxicology · doi:10.1016/j.neuro.2014.01.001 · Cited by 71 · see citing works
“, 2008), and are involved in AD-associated inflammation and astrogliosis (Selkoe, 2001; Mattson, 2004; Farfara et al., 2008).”
BackgroundTribouillard‐Tanvier, D., Striebel, J. F., Peterson, K. E., & Chesebro, B. W. (2009) · Journal of Virology · doi:10.1128/jvi.01413-09 · Cited by 68 · see citing works
“This conundrum has been faced in other neurodegenerative and neuroinflammatory diseases, such as Alzheimer’s disease (20), amyotrophic lateral sclerosis (4), Parkinson’s disease (51), and multiple sclerosis (13).”
BackgroundLana, D., Iovino, L., Nosi, D., Wenk, G. L., & Giovannini, M. G. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.07.011 · Cited by 66 · see citing works
Wang, Y., Li, M., Tang, J., Song, M., Xu, X., Xiong, J., Li, J., & Bai, Y. (2011) · Endocrinology · doi:10.1210/en.2011-0145 · Cited by 65 · see citing works
Fitting, S., Zou, S., Chen, W., Vo, P., Hauser, K. F., & Knapp, P. E. (2010) · Journal of Proteome Research · doi:10.1021/pr900926n · Cited by 62 · see citing works
Guzmán, B. C., Chaffey, T. E., Palpagama, T. H., Waters, S., Boix, J., Tate, W. P., Peppercorn, K., Dragunow, M., Waldvogel, H. J., Faull, R. L. M., et al. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.552073 · Cited by 59 · see citing works
The effects of amyloid-β42 oligomer on the proliferation and activation of astrocytes in vitro
Hou, L., Liu, Y., Wang, X., Ma, H., He, J., Zhang, Y., Yu, C.-H., Guan, W., & Ma, Y.-H. (2011) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-011-9439-y · Cited by 57 · see citing works
“Astrocytes, the biggest and the most abundant glial cell type in the central nervous system (Dan et al. 2008), play an important role in normal physiological functioning, e.g., the absorption of neurotransmitters, the synthesis and secretion of trophic factors, etc. (Takuma et al. 2004; Lü et al.…”
Backgroundγ‐Secretase component presenilin is important for microglia β‐amyloid clearance
Farfara, D., Trudler, D., Segev‐Amzaleg, N., Galron, R., Stein, R., & Frenkel, D. (2010) · Annals of Neurology · doi:10.1002/ana.22191 · Cited by 56 · see citing works
“ANNALS of Neurology 176 Volume 69, No. 1 Discussion We have demonstrated for the first time a dual role for c-secretase in the pathogenesis of AD.”
BackgroundInfluentialSelf-citationLam, D. Y., Jim, J., To, E. C., Rasmussen, C. A., Kaufman, P. L., & Matsubara, J. A. (2009) · Europe PMC (PubMed Central) · Cited by 57 · see citing works
The Potential Roles of Aquaporin 4 in Alzheimer’s Disease
Lan, Y., Zhao, J., Ma, T., & Li, S. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9446-1 · Cited by 56 · see citing works
Oboh, G., Adebayo, A. A., Ademosun, A. O., & Olowokere, O. G. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.12.008 · Cited by 56 · see citing works
Characterization of potent anticholinesterase plant oil based microemulsion
Chaiyana, W., Saeio, K., Hennink, W. E., & Okonogi, S. (2010) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2010.09.005 · Cited by 55 · see citing works
“This disease is associated with intellectual misfunction and ubsequent decline in cognitive, behavioral and motor functions Farfara et al., 2008).”
BackgroundGain in Brain Immunity in the Oldest-Old Differentiates Cognitively Normal from Demented Individuals
Katsel, P., Tan, W., & Haroutunian, V. H. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007642 · Cited by 55 · see citing works
“One parsimonious interpretation of the expression of immune system marker genes in the oldest-old is that a robust immune system is essential for the maintenance of cognitive health to very old age [35,69,70], and that a failure of this system to respond to activating stimuli may contribute to the development of demen…”
BackgroundYaghmaei, P., Azarfar, K., Dezfulian, M., & Ebrahim‐Habibi, A. (2014) · DARU Journal of Pharmaceutical Sciences · doi:10.1186/2008-2231-22-24 · Cited by 55 · see citing works
“The flavonoid silibinin (or sylibin) [(2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2(hydroxy-methyl)-2,3-dihydrobenzo[b][1,4]doxin-6-yl] chroman-4-one] is the main compound of the herb milk thistle (Silybum marianum) extract (silymarin) [11].”
Microglial activation depends on beta‐amyloid conformation: role of the formylpeptide receptor 2
Heurtaux, T., Michelucci, A., Losciuto, S., Gallotti, C., Felten, P., Dorban, G., Grandbarbe, L., Morga, E., & Heuschling, P. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06783.x · Cited by 54 · see citing works
“A large number of glial cell surface receptors are known to mediate interaction with the Ab peptide (Farfara et al. 2008).”
BackgroundRole of pattern recognition receptors of the neurovascular unit in inflamm-aging
Wilhelm, I., Nyúl-Tóth, Á., Kozma, M., Farkas, A. E., & Krizbai, I. A. (2017) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00106.2017 · Cited by 56 · see citing works
“In addition, astrocytes are a common source of inflammatory mediators in brain pathologies (43).”
BackgroundYoshida, H., Meng, P., Matsumiya, T., Tanji, K., Hayakari, R., Xing, F., Wang, L. Y., Tsuruga, K., Tanaka, H., Mimura, J., et al. (2013) · Neuroscience Research · doi:10.1016/j.neures.2013.11.004 · Cited by 51 · see citing works
“neurodegenerative roles of astrocytes exposed to hypoxia or reoxygenation in patients with both AD and stroke (Farfara et al., 2008; Li et al., 2011; Yoshida et al., 2005), it is also a revealing fact that the A release from the cells treated with CA was suppressed under not only normoxia but also hypoxia or reoxygena…”
The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity
Li, E., Noda, M., Doi, Y., Parajuli, B., Kawanokuchi, J., Sonobe, Y., Takeuchi, H., Mizuno, T., & Suzumura, A. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-148 · Cited by 51 · see citing works
“In neurodegenerative diseases, such as AD and Parkinson’s disease, microglia accumulate in lesions where they are thought to have both neurotoxic and neuroprotective functions [9].”
BackgroundUgolini, F., Lana, D., Nardiello, P., Nosi, D., Pantano, D., Casamenti, F., & Giovannini, M. G. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00372 · Cited by 50 · see citing works
Zaheer, S. A., Thangavel, R., Wu, Y., Khan, M. M., Kempuraj, D., & Zaheer, A. (2012) · Neurochemical Research · doi:10.1007/s11064-012-0913-z · Cited by 50 · see citing works
“Activated glia are known to secrete proinflammatory cytokines and other toxic substances capable of causing neuronal death [26–28].”
Wu, Y., Pang, J., Peng, J., Cao, F., Vitek, M. P., Li, F., Jiang, Y. Q., & Sun, X. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.05.058 · Cited by 50 · see citing works
RetractedJiang, T., Luo, J., Pan, X., Zheng, H., Yang, H., Zhang, L., & Hu, X. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119526 · Cited by 50 · see citing works
Anwar, M. M. (2021) · Cell Biochemistry and Function · doi:10.1002/cbf.3673 · Cited by 53 · see citing works
Characterization of brain lesions in a mouse model of progressive multiple sclerosis
Levy, H., Assaf, Y., & Frenkel, D. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.08.017 · Cited by 50 · see citing works
“Glia cells maintain brain plasticity, protect the brain during functional recovery from injury, and, once properly activated, are the first defense against the pathologic abnormalities of neurodegenerative diseases (Farfara et al., 2008).”
Self-citationPKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease
Morel, M., Couturier, J., Lafay‐Chebassier, C., Paccalin, M., & Page, G. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00849.x · Cited by 47 · see citing works
“Thelper 1 cells can promote microglial cell activation through the secretion of IFN- , which also up-regulates the expression major histocompatibility complex class II molecules by microglial cells, thereby enhancing the interaction between T cells and microglial cells [164, 165].”
BackgroundSweepers in the CNS: Microglial Migration and Phagocytosis in the Alzheimer Disease Pathogenesis
Noda, M., & Suzumura, A. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/891087 · Cited by 47 · see citing works
“Microglia accumulate in the lesions of a variety of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease, and multiple sclerosis, and are thought to play both toxic and protective functions for neuronal survival [1].”
BackgroundNeurobiological aspects of Alzheimer's disease
Chopra, K., Misra, S., & Kuhad, A. (2011) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.557363 · Cited by 46 · see citing works
“Several amyloid peptides and APP can act as potent glial activators [75], and disruption of the APP gene and its proteolytic products delay and decrease microglial activation [76].”
BackgroundKovács, A., Saje, A., Wong, A. P., Szénási, G., Kiricsi, P., Szabó, É. R., Cooper, J. D., & Pearce, D. A. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.10.010 · Cited by 46 · see citing works
“Activation of glial cells in general is a common event in neurodegenerative diseases (Danton and Dietrich, 2003; Farfara et al., 2008; Venneti et al., 2009), and several previous studies have shown that glial activation also occurs in Batten disease.”
In Vitro and In Vivo Activation of Astrocytes by Amyloid-β is Potentiated by Pro-Oxidant Agents
García‐Matas, S., de Vera, N., Aznar, A. O., Marimon, J. M., Adell, A., Planas, A. M., Cristòfol, R. M., & Sanfeliu, C. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1365 · Cited by 45 · see citing works
“In advanced stages of AD pathology, these chronic astrocyte alterations of oxidative stress and inflammation will further impair neuron functionality and contribute to the degenerative process [67,68].”
Folch, J., Patraca, I., Martínez, N., Pedrós, I., Petrov, D., Ettcheto, M., Abad, S., Marin, M., Beas-Zarate, C., & Camins, A. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.05.002 · Cited by 48 · see citing works
Lee, A. Y., Lee, M. H., Lee, S., & Cho, E. J. (2018) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.8b00836 · Cited by 43 · see citing works
Neuron‐glia interactions: Molecular basis of alzheimer’s disease and applications of neuroproteomics
Ibrahim, A. M., Pottoo, F. H., Dahiya, E. S., Khan, F. A., & Kumar, J. B. S. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14838 · Cited by 45 · see citing works
“…microglia, reactive astrocytes, progressive synaptic dysfunction and neuronal death in advanced chronic states found majorly in the hippocampus points towards AD (Bedner et al., 2015; Farfara et al., 2008; Hemonnot, Hua, Ulmann, & Hirbec, 2019; Kosik, 1991; Sharoar, Hu, Ma, Zhu, & Yan, 2019).”
BackgroundMoreno‐González, I., Baglietto‐Vargas, D., Sanchez-Varo, R. M., Jiménez, S., Trujillo‐Estrada, L., Sánchez‐Mejías, E., del Río, J. C., Torres, M., Romero‐Acebal, M., Ruano, D., et al. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1192 · Cited by 42 · see citing works
Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease
Kovács, A., Saje, A., Wong, A. P., Ramji, S., Cooper, J. D., & Pearce, D. A. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.05.040 · Cited by 42 · see citing works
“Activation of astrocytes and microglial cells is a fairly common event in neurodegenerative disorders including Batten disease (Danton and Dietrich, 2003; Farfara et al., 2008; Venneti et al., 2009).”
Background
- Authors
- Farfara, D., Lifshitz, V., & Frenkel, D.
- Affiliations
- Tel Aviv University (IL)
- Corresponding author
- Frenkel, D.
- Venue
- Journal of Cellular and Molecular Medicine
- Publisher
- Wiley
- Published
- 2008-05-21
- Volume
- 12
- Issue
- 3
- Pages
- 762-780
- ISSN
- 1582-1838 (ISSN-L)
- 1582-4934
- PMC
- PMC4401126
- OpenAlex
- W2022388884
- Cited by
- 216
- References
- 202
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 13 · 2019: 5 · 2018: 7 · 2017: 9 · 2016: 7 · 2015: 8 · 2014: 15 · 2013: 15 · 2012: 20
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular and Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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, glial cells, microglia, astrocytes, neuroinflammation, innate immune response, amyloid-beta, neurofibrillary tangles, amyloid plaques, complement system, cytokines and chemokines, neuroprotection, neurotoxicity, neurodegeneration, anti-inflammatory therapy
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Astrocytes, Brain, Disease Models, Animal, Humans, Models, Neurological, Synaptic Transmission, Synapses, T-Lymphocytes, Amyloid beta-Peptides, Microglia, Endothelial Cells, Plaque, Amyloid
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