The DOI matches its Crossref record; 66 of the 66 references it cites were found in a registry or an index.
Reactive glia show increased immunoproteasome activity in Alzheimer’s disease
Abstract
The proteasome is the major protein degradation system within the cell, comprised of different proteolytic subunits; amyloid-β is thought to impair its activity in Alzheimer's disease. Neuroinflammation is a prominent hallmark of Alzheimer's disease, which may implicate an activation of the immunoproteasome, a specific proteasome variant induced by immune signalling that holds slightly different proteolytic properties than the constitutive proteasome. Using a novel cell-permeable proteasome activity probe, we found that amyloid-β enhances proteasome activity in glial and neuronal cultures. Additionally, using a subunit-specific proteasome activity assay we showed that in the cortex of the APPswePS1dE9 plaque pathology mouse model, immunoproteasome activities were strongly increased together with increased messenger RNA and protein expression in reactive glia surrounding plaques. Importantly, this elevated activity was confirmed in human post-mortem tissue from donors with Alzheimer's disease. These findings are in contrast with earlier studies, which reported impairment of proteasome activity in human Alzheimer's disease tissue and mouse models. Targeting the increased immunoproteasome activity with a specific inhibitor resulted in a decreased expression of inflammatory markers in ex vivo microglia. This may serve as a potential novel approach to modulate sustained neuroinflammation and glial dysfunction associated with Alzheimer's disease.
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“Conversely, the proteasome subunit (Psmb8) and matrix metalloproteinase-12 (Mmp12) are associated with detrimental roles in the brain [25,26].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [25]
Citations
Cites
Vandesompele, J., De Preter, K., Pattyn, F., Poppe, B., Van Roy, N., De Paepe, A., & Speleman, F. (2002) · Genome Biology · doi:10.1186/gb-2002-3-7-research0034 · Cited by 20,038
Neuropathological stageing of Alzheimer-related changes.
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Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063
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Protein degradation and protection against misfolded or damaged proteins.
Goldberg, A. L. (2003) · Nature · doi:10.1038/nature02263 · Cited by 2,088
Microglia in neurodegenerative disease
Perry, V. H., Nicoll, J. A. R., & Holmes, C. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.17 · Cited by 1,543
Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice
Hickman, S. E., Allison, E. K., & El Khoury, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0616-08.2008 · Cited by 1,329 · cited 3×
“Sustained immune signalling has previously been shown to lead to reduced levels of amyloid-b recognition receptors and of amyloidb degrading enzymes in microglia from aged Alzheimer’s disease mice (Hickman et al., 2008), as well as a reduction of general cognitive functions (Corona et al., 2011).”
BackgroundImpaired Proteasome Function in Alzheimer's Disease
Keller, J. N., Hanni, K. B., & Markesbery, W. R. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0750436.x · Cited by 848
CD14 is required for MyD88-independent LPS signaling
Jiang, Z., Georgel, P., Du, X., Shamel, L., Sovath, S., Mudd, S., Huber, M., Kalis, C., Keck, S., Galanos, C., et al. (2005) · Nature Immunology · doi:10.1038/ni1207 · Cited by 683
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Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226
Reactive astrocyte nomenclature, definitions, and future directions
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00783-4 · Cited by 2,513
Self-citationAstrocyte reactivity and reactive astrogliosis: costs and benefits
Pekny, M., & Pekna, M. (2014) · Physiological Reviews · doi:10.1152/physrev.00041.2013 · Cited by 934
Hol, E. M., & Pekny, M. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2015.02.004 · Cited by 917
Self-citationAstrocytes: a central element in neurological diseases
Pekny, M., Pekna, M., Messing, A., Steinhäuser, C., Lee, J., Parpura, V., Hol, E. M., Sofroniew, M. V., & Verkhratsky, A. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1513-1 · Cited by 793
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Metadata
- Authors
- Orre, M., Kamphuis, W., Dooves, S., Kooijman, L., Chan, E. T., Kirk, C. J., Dimayuga Smith, V., Koot, S., Mamber, C., Jansen, A. H., Ovaa, H., & Hol, E. M.
- Affiliations
- Netherlands Institute for Neuroscience (NL)
- The Netherlands Cancer Institute (NL)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-04-19
- Volume
- 136
- Issue
- 5
- Pages
- 1415-1431
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2034724560
- Cited by
- 180
- References
- 66
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 14 · 2023: 16 · 2022: 10 · 2021: 17 · 2020: 11 · 2019: 19 · 2018: 13 · 2017: 11 · 2016: 14 · 2015: 10 · 2014: 14 · 2013: 5
- FWCI
- 9.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- VU Research Portal (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- immunoproteasome, Alzheimer's disease, reactive glia, neuroinflammation, amyloid-beta, proteasome activity, microglia, amyloid plaques, proteasome inhibitors, glial dysfunction
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Cells, Cultured, Enzyme Activation, Female, Humans, Male, Mice, Transgenic, Middle Aged, Neuroglia, Tumor Cells, Cultured, Proteasome Endopeptidase Complex, Mice
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