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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Psmb8 and Mmp12 are associated with detrimental roles in the brain.
“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]
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“Conversely, the pro easome subunit (Psmb8) and matrix met lloproteinase-12 (Mmp12) are associated with detrimental roles in the brain [25,26].”
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- 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
- Health Sciences › Medicine › Physiology › 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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