β-Amyloid Activates the O⨪2 Forming NADPH Oxidase in Microglia, Monocytes, and Neutrophils
Open accessAbstract
The deposition of beta-amyloid in the brain is the key pathogenetic event in Alzheimer's disease. Among the various mechanisms proposed to explain the neurotoxicity of beta-amyloid deposits, a new one, recently identified in our and other laboratories, suggests that beta-amyloid is indirectly neurotoxic by activating microglia to produce toxic inflammatory mediators such as cytokines, nitric oxide, and oxygen free radicals. Three findings presented here support this mechanism, showing that beta-amyloid peptides (25-35), (1-39), and (1-42) activated the classical NADPH oxidase in rat primary culture of microglial cells and human phagocytes: 1) The exposure of the cells to beta-amyloid peptides stimulates the production of reactive oxygen intermediates; 2) the stimulation is associated with the assembly of the cytosolic components of NADPH oxidase on the plasma membrane, the process that corresponds to the activation of the enzyme; 3) neutrophils and monocytes of chronic granulomatous disease patients do not respond to beta-amyloid peptides with the stimulation of reactive oxygen intermediate production. Data are also presented that the activation of NADPH oxidase requires that beta-amyloid peptides be in fibrillary state, is inhibited by inhibitors of tyrosine kinases or phosphatidylinositol 3-kinase and by dibutyryl cyclic AMP, and is potentiated by interferon-gamma or tumor necrosis factor-alpha.
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Microglia express the full set of specific proteins that compose the phagocyte oxidase (Nox2, p22phox, p47phox, p40phox, p67phox, and Rac).
“Previous studies have shown that microglia express the full set of specific proteins that compose the phagocyte oxidase (Nox2, p22 phox , p47 phox , p40 phox , p67 phox , and Rac) (Bianca et al., 1999)”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Bianca et al., 1999
The Results section (page unavailable) lists gp91phox (Nox2), p22phox, p47phox, p40phox, p67phox, and Rac as components of the classical NADPH oxidase, which the paper reports is activated in microglia. It does not demonstrate expression of every listed protein in microglia: the Results state that testing oxidase-component translocation in rat microglia was not feasible because suitable antibodies were unavailable. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia express the phagocyte NADPH oxidase.
“Like other phagocytes, microglia express the phagocyte NADPH oxidase (Sankarapandi et al., 1998;Bianca et al., 1999)”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Bianca et al., 1999
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Cites
Amyloid deposition as the central event in the aetiology of Alzheimer’s disease
Hardy, J., & Allsop, D. (1991) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(91)90609-v · Cited by 2,538 · see citing works
RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease
Yan, S. D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., et al. (1996) · Nature · doi:10.1038/382685a0 · Cited by 2,012 · see citing works
Activation of microglial cells by β-amyloid protein and interferon-γ
Meda, L., Cassatella, M. A., Szendrei, G. I., Otvos, L., Baron, P., Villalba, M., Ferrari, D., & Rossi, F. (1995) · Nature · doi:10.1038/374647a0 · Cited by 1,314 · see citing works
Self-citationHensley, K., Carney, J. M., Mattson, M. P., Aksenova, M., Harris, M., Wu, J. F., Floyd, R. A., & Butterfield, D. A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.8.3270 · Cited by 1,086 · see citing works
Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils
Khoury, J. E., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C., & Loike, J. D. (1996) · Nature · doi:10.1038/382716a0 · Cited by 727 · see citing works
Induction of phagocyte cytochrome b heavy chain gene expression by interferon gamma.
Newburger, P. E., Ezekowitz, R. A., Whitney, C., Wright, J., & Orkin, S. H. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.14.5215 · Cited by 140 · see citing works
Van Muiswinkel, F. L., Veerhuis, R., & Eikelenboom, P. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.66062468.x · Cited by 85 · see citing works
Flagged first, then by citations
Research works printed but not linked: 7
- Kirschner, D. A., Abraham, C., and Selkoe, D. J. (1986) Proc. Natl. Acad. Sci.
- Lorenzo, A., and Yankner, B. A. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 12243-12247
- Schubert, D., Behl, C. Lesley, R., Brack, A., Dargusch, R., Sagara, Y., and Kimura, H. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 1989 -1993
- Hensley, K., Carney, J. M., Mattson, M. P., Aksenova, M., Harris, M., Wu, J. F., and Floyd, R. A. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 3270 -3274
- Woodroofe, M. N., and Cuzner M. L. (1995) in Neural Cell Culture (Cohen, J., and Wilkin, G. P, eds) pp. 107-119, IRL Press, Oxford
- Cassatella, M., Bazzoni, F., Amezaga, M. A., and Rossi, F. (1991) Biochem. Soc. Trans. 19, 63-68
- Newburger, P. E., Ezekowitz, R. A. B., Whitney C., Wright, J., and Orkin, S. H. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 5215-5219
Cited by
Sorted by citations
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514 · see citing works
Neurovascular regulation in the normal brain and in Alzheimer's disease
Iadecola, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1387 · Cited by 2,213 · see citing works
Halliwell, B. (2001) · Drugs & Aging · doi:10.2165/00002512-200118090-00004 · Cited by 1,502 · see citing works
Simpson, D. S. A., & Oliver, P. L. (2020) · Antioxidants · doi:10.3390/antiox9080743 · Cited by 1,044 · see citing works
Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes
Nortley, R., Korte, N., Izquierdo, P., Hirunpattarasilp, C., Mishra, A., Jaunmuktane, Z., Kyrargyri, V., Pfeiffer, T., Khennouf, L., Madry, C., et al. (2019) · Science · doi:10.1126/science.aav9518 · Cited by 682 · see citing works
Microglial 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 · see citing works
Abramov, A. Y., Canevari, L., & Duchen, M. R. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.4042-03.2004 · Cited by 587 · see citing works
Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease
Cai, Z., Hussain, M. D., & Yan, L.-J. (2014) · International Journal of Neuroscience · doi:10.3109/00207454.2013.833510 · Cited by 583 · see citing works
NADPH oxidase in brain injury and neurodegenerative disorders
Ma, M. W., Wang, J., Zhang, Q., Wang, R., Dhandapani, K. M., Vadlamudi, R. K., & Brann, D. W. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0150-7 · Cited by 432 · see citing works
Coraci, I. S., Husemann, J., Berman, J. W., Hulette, C., Dufour, J. H., Campanella, G. K., Luster, A. D., Silverstein, S. C., & El Khoury, J. B. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64354-4 · Cited by 398 · see citing works
The 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
The role of oxidative stress in the toxicity induced by amyloid β-peptide in Alzheimer’s disease
Miranda, S., Opazo, C., Larrondo, L. F., Muñoz, F. J., Ruiz, F., Leighton, F., & Inestrosa, N. C. (2000) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00015-0 · Cited by 369 · see citing works
Immunology 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
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Shimohama, S., Tanino, H., Kawakami, N., Okamura, N., Kodama, H., Yamaguchi, T., Hayakawa, T., Nunomura, A., Chiba, S., Perry, G., et al. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2897 · Cited by 292 · see citing works
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Goldberg, E. L., & Dixit, V. D. (2015) · Immunological Reviews · doi:10.1111/imr.12295 · Cited by 274 · see citing works
Park, L., Anrather, J., Zhou, P., Frys, K., Pitstick, R., Younkin, S., Carlson, G. A., & Iadecola, C. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.5207-04.2005 · Cited by 244 · see citing works
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Chéret, C., Gervais, A., Lelli, A., Colin, C., Amar, L., Ravassard, P., Mallet, J., Cumano, A., Krause, K.-H., & Mallat, M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3568-08.2008 · Cited by 225 · see citing works
Aβ-peptides enhance vasoconstriction in cerebral circulation
Niwa, K., Porter, V. A., Kazama, K., Cornfield, D., Carlson, G. A., & Iadecola, C. (2001) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.281.6.h2417 · Cited by 202 · see citing works
Niwa, K., Carlson, G. A., & Iadecola, C. (2000) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200012000-00005 · Cited by 191 · see citing works
Haslund‐Vinding, J., McBean, G., Jaquet, V, & Vilhardt, F. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13425 · Cited by 169 · see citing works
Park, L., Wang, G., Zhou, P., Zhou, J., Pitstick, R., Previti, M. L., Younkin, L., Younkin, S. G., Van Nostrand, W. E., Cho, S., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1015413108 · Cited by 156 · see citing works
Erickson, M. A., Hartvigson, P. E., Morofuji, Y., Owen, J. B., Butterfield, D. A., & Banks, W. A. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-150 · Cited by 145 · see citing works
PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET
Venneti, S., Lopresti, B. J., Wang, G., Hamilton, R. L., Mathis, C. A., Klunk, W. E., Apte, U. M., & Wiley, C. A. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.11.005 · Cited by 138 · see citing works
Schilling, T., & Eder, C. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22675 · Cited by 117 · see citing works
Guedes, J. R., Lao, T., Cardoso, A. L., & El Khoury, J. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00549 · Cited by 115 · see citing works
Vascular and metabolic dysfunction in Alzheimer’s disease: a review
Murray, I. V. J., Proza, J. F., Sohrabji, F., & Lawler, J. M. (2011) · Experimental Biology and Medicine · doi:10.1258/ebm.2011.010355 · Cited by 104 · see citing works
Cognitive impairment in humanized APP×PS1 mice is linked to Aβ1–42 and NOX activation
Bruce-Keller, A. J., Gupta, S., Knight, A. G., Beckett, T. L., McMullen, J. M., Davis, P. R., Murphy, M. P., Van Eldik, L. J., St Clair, D., & Keller, J. N. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.07.012 · Cited by 96 · see citing works
The Plasma Membrane: A Platform for Intra- and Intercellular Redox Signaling
Nordzieke, D. E., & Medraño-Fernandez, I. (2018) · Antioxidants · doi:10.3390/antiox7110168 · Cited by 90 · see citing works
Neuroinflammation in Alzheimer’s disease: Pleiotropic roles for cytokines and neuronal pentraxins
Swanson, A., Wolf, T., Sitzmann, A., & Willette, A. A. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.02.015 · Cited by 72 · see citing works
Anti-inflammatory and Immune Therapy for Alzheimers Disease: Current Status and Future Directions
Walker, D., & Lue, L.-F. (2007) · Current Neuropharmacology · doi:10.2174/157015907782793667 · Cited by 66 · see citing works
- Authors
- Della Bianca, V., Dusi, S., Bianchini, E., Dal Prà, I., & Rossi, F.
- Affiliations
- University of Verona (IT)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-05
- Volume
- 274
- Issue
- 22
- Pages
- 15493-15499
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2101955048
- Cited by
- 324
- References
- 7
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 10 · 2021: 10 · 2020: 9 · 2019: 8 · 2018: 8 · 2017: 10 · 2016: 7 · 2015: 8 · 2014: 9 · 2013: 14 · 2012: 14
- FWCI
- 11.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- amyloid-beta, NADPH oxidase, reactive oxygen species, microglia, monocytes, neutrophils, Alzheimer's disease, chronic granulomatous disease, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase, interferon-gamma, TNF-α, neuroinflammation, phagocyte activation
- MeSH terms
- Animals, Cell Membrane, Bucladesine, Enzyme Activation, Heparan Sulfate, Humans, Hydrogen Peroxide, Interferon-gamma, Monocytes, Neutrophils, Peptide Fragments, Tetradecanoylphorbol Acetate, Tumor Necrosis Factor-alpha, Amyloid beta-Peptides, Rats, Wistar, Reactive Oxygen Species, Microglia, NADPH Oxidases, Rats
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