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.

Silencing of Inducible Immunoproteasome Subunit Expression by Chemically Modified siRNA and shRNA

“…[12] There are data providing evidence that Alzheimer's disease is linked to increased expression of immunosubunits in reactive glia in human post-mortem tissue from donors with Alzheimer's disease compared with healthy controls. [13] The same results were observed in the case of Huntington disease. [14] Most well-characterized proteasome inhibitors equivalently reduce expression of both constitutive and inducible proteasome subunits and possess considerable toxicities that may limit their clinical utility.…”

“…[11,12,14,27] Specific inhibition of LMP2, LMP7, and MECL-1 gene expression might be used for the treatment of these diseases. [1,13] However, most well-characterized proteasome inhibitors mediate equivalent inhibition of both immunoproteasome and constitutive proteasome subunits and possess considerable toxicity that restricts their clinical application. [28,29] For example, nonselective proteasome inhibitors Bortezomib and Carfilzomib are approved by FDA for clinical usage in the treatment of multiple myeloma.…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…A previous study has also demonstrated that the reactive glial shows increased immunoproteasome activity in AD to clear Aβ accumulation (Orre, Kamphuis, Dooves, Kooijman, & Chan, 2013), but the underlying mechanism is not well defined. More interesting, recent studies found a novel microglia cell type associated with neurodegenerative diseases (DAM cells) using single‐cell RNA‐seq technology, which displayed a unique capability to clear Aβ (Keren‐Shaul, Spinrad, Weiner, Matcovitch‐Natan, & Dvir‐Szternfeld, 2017).…”

Potential Application of Tetrahydroxystilbene Glucoside in Treatment of Alzheimer’s Disease

“…Other studies found that TSG facilitated tetanus stimulationinduced hippocampal long-term potentiation through activation of NMDA receptor in the hippocampal CA1 region of normal mice; phosphorylation of CaMKII and activation of ERK1/2 cascades possibly mediated TSG-induced enhancement [76] . There are also investigations suggested that TSG attenuated lipopolysaccharide (LPS)-mediated induction of pro-inflammatory factors in microglia through reducing binding activity of NF-κB [57] , and attenuated LPSinduced NADPH oxidase activation and subsequent reactive oxygen species production [49] ; while microglia are believed to mediate development of AD and that neurons injury is usually secondary to microglia activation [77][78][79][80] . …”