Immunoproteasome deficiency alters microglial cytokine response and improves cognitive deficits in Alzheimer’s disease-like APPPS1 mice

Abstract

The immunoproteasome (iP) represents a specialized type of proteasomes, which plays an important role in the clearance of oxidant-damaged proteins under inflammatory and pathological conditions determining the outcome of various diseases. In Alzheimer’s disease (AD)-like APPPS1 mice Aβ-deposition is paralleled by iP upregulation, most likely mediated through type I interferon induction. To define the impact of increased iP expression we crossed APPPS1 mice with mice deficient in the iP subunit LMP7 resulting in impaired iP function. While LMP7 deficient APPPS1 mice showed no major change in cerebral Aβ-pathology, we observed an altered cytokine response in microglia isolated from LMP7 deficient APPPS1 mice compared to LMP7 expressing APPPS1 control mice. The altered microglial cytokine profile upon iP deficiency in the presence of extracellular Aβ-pathology was associated with an improvement of Aβ-associated cognitive deficits typically present in APPPS1 mice. Our findings suggest a role for iP in the regulation of the innate immune response towards extracellular Aβ-pathology and indicate that inhibition of iP function can modulate the cognitive phenotype upon overexpression of Aβ.

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

“…The immunoproteasome is an alternative UPS isoform implicated in antigen (Ag) processing and presentation, which operates constitutively in immune cells while being induced by pro-inflammatory and oxidative stimuli in almost any other cell type [104][105][106][205][206][207][208][209][210][211]. In fact, the immunoproteasome is significantly upregulated in reactive astrocytes, microglia, and neurons in both patients and experimental models of neurodegeneration [104][105][106][205][206][207][208][209][210][211][212][213]. Compared with standard proteasome, the immunoproteasome owns enhanced chymotrypsin-like activity and structural peculiarities which enable fast and efficient processing of endogenous, microbial-and misfold/aggregation-prone-proteins [104,[206][207][208].…”

“…Compared with standard proteasome, the immunoproteasome owns enhanced chymotrypsin-like activity and structural peculiarities which enable fast and efficient processing of endogenous, microbial-and misfold/aggregation-prone-proteins [104,[206][207][208]. In fact, the immunoproteasome is recruited as a compensatory, protective attempt to cope with protein overload and cellular stress when standard UPS is impaired, thus contributing to the regulation of misfolded protein-driven innate immune responses [105,207,208,211]. Immune adaptation of the UPS is a tightly regulated and transient response, as cells rapidly need to switch back to standard UPS once immunoproteasome function is no longer required [214].…”

“…Immune adaptation of the UPS is a tightly regulated and transient response, as cells rapidly need to switch back to standard UPS once immunoproteasome function is no longer required [214]. Nonetheless, under persistent inflammatory and oxidative stimuli which occur during protein aggregation and spreading, the immunoproteasome may abnormally persist within glial and neuronal cells, fueling a vicious cycle of inflammatory and immune reactions in the CNS [104,211].…”

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

“…Microglia are the primary inflammatory mediators of the central nervous system and, as other immune cells, exhibit a constitutive expression of both standard proteasomes and immunoproteasomes (1,22,25). Hence, to assess the impact of proteasome impairment, we first treated primary mice microglia with either the immunoproteasome-specific inhibitor ONX-0914 (39) or bortezomib, which inhibits both types of proteasome (40).…”

“…Upon induction of ER stress, these sentinels reestablish proteostasis by controlling protein translation and increasing folding capacity (18). Impairment of proteasomal function, reflected by intra-and extracellular protein aggregates, accompanied by disturbance of ER homeostasis as well as progressive tissue degeneration, is a hallmark of progressive neurodegenerative diseases (19)(20)(21)(22). In particular, several studies emphasize the role of microglia and, in particular, microglial proteasomes as potential mediators of the immune response that drives neurodegeneration or neuroinflammation (23)(24)(25)(26).…”