Reactive glia show increased immunoproteasome activity in Alzheimer's disease

• Published in: Brain (London, England : 1878) Vol. 136; no. Pt 5; pp. 1415 - 1431
• Main Authors: ORRE, Marie, KAMPHUIS, Willem, OVAA, Huib, HOL, Elly M, DOVES, Stephanie, KOOIJMAN, Lieneke, CHAN, Elena T, KIRK, Christopher J, SMITH, Vanessa Dimayuga, KOOT, Sanne, MAMBER, Carlyn, JANSEN, Anne H
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2013
• Subjects: Adult; Aged; Aged, 80 and over; Alzheimer Disease - immunology; Alzheimer Disease - metabolism; Animals; Biological and medical sciences; Cells, Cultured; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Enzyme Activation - immunology; Female; Humans; Male; Medical sciences; Mice; Mice, Transgenic; Middle Aged; Neuroglia - immunology; Neuroglia - metabolism; Neurology; Proteasome Endopeptidase Complex - metabolism; Tumor Cells, Cultured; Nervous system diseases; immunoproteasome; Alzheimer disease; neuroinflammation; Neuroglia; Central nervous system disease; Degenerative disease; Astrocyte; astrocytes; Alzheimer's disease; Cerebral disorder; Microglia
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awt083

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.