title: 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.
authors.affiliation: Astrocyte Biology and Neurodegeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.
authors.forename: Marie
authors.initials: M
authors.lastname: Orre
authors.forename: Willem
authors.initials: W
authors.lastname: Kamphuis
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dooves
authors.forename: Lieneke
authors.initials: L
authors.lastname: Kooijman
authors.forename: Elena T
authors.initials: ET
authors.lastname: Chan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kirk
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dimayuga Smith
authors.forename: Sanne
authors.initials: S
authors.lastname: Koot
authors.forename: Carlyn
authors.initials: C
authors.lastname: Mamber
authors.forename: Anne H
authors.initials: AH
authors.lastname: Jansen
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.forename: Elly M
authors.initials: EM
authors.lastname: Hol
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D046988:Proteasome Endopeptidase Complex