A dual inhibitor of the proteasome catalytic subunits LMP2 and Y attenuates disease progression in mouse models of Alzheimer\u2019s disease

In Jun Yeo,Ahruem Baek,Yun Kyung Kim,Hyun Jung Jeong,Deepak Bhattarai,Zachary Miller,Kyung Bo Kim,Dong-Eun Kim,Yu Mi Baek,Jin Tae Hong,Min Jae Lee

doi:10.1038/s41598-019-54846-z

Abstract

The immunoproteasome (iP) is a variant of the constitutive proteasome (cP) that is abundantly expressed in immune cells which can also be induced in somatic cells by cytokines such as TNF-α or IFN-γ. Accumulating evidence support that the iP is closely linked to multiple facets of inflammatory response, eventually leading to the development of several iP inhibitors as potential therapeutic agents for autoimmune diseases. Recent studies also found that the iP is upregulated in reactive glial cells surrounding amyloid β (Aβ) deposits in brains of Alzheimer’s disease (AD) patients, but the role it plays in the pathogenesis of AD remains unclear. In this study, we investigated the effects of several proteasome inhibitors on cognitive function in AD mouse models and found that YU102, a dual inhibitor of the iP catalytic subunit LMP2 and the cP catalytic subunit Y, ameliorates cognitive impairments in AD mouse models without affecting Aβ deposition. The data obtained from our investigation revealed that YU102 suppresses the secretion of inflammatory cytokines from microglial cells. Overall, this study indicates that there may exist a potential link between LMP2/Y and microglia-mediated neuroinflammation and that inhibition of these subunits may offer a new therapeutic strategy for AD.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia in the elderly and presents one of the greatest health-care challenges further exacerbated by an aging global population
This result is interesting in that LMP2/Y inhibitors or genetic knockout previously had no impact on inflammatory responses in human peripheral blood mononuclear cells or mouse peritoneal macrophages[38,39]
We showed that the LMP2/Y dual inhibitor YU102 ameliorates cognitive deficits in mouse models of AD, independent of amyloid β (Aβ) deposition or tau aggregation

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia in the elderly and presents one of the greatest health-care challenges further exacerbated by an aging global population. Studies demonstrate that inhibition of LMP7 activity leads to suppression of pro-inflammatory cytokine release in human tissues such as T-cells, B-cells, neutrophils, or monocytes[14,15] This function led to the development of several LMP7 inhibitors as potential therapeutic agents for inflammatory diseases. Studies found that LMP2 and LMP7 are upregulated at both the mRNA and protein levels in plaque-associated microglia and astrocytes from AD mice[29,30,31,32] These findings have been confirmed in post-mortem human AD brains where levels of active iP but not cP subunits are increased relative to control samples[30,33], suggesting a potential link between the iP and AD pathogenesis. Our current results suggest that the proteasome catalytic subunits LMP2 and Y are closely linked to microglia-mediated inflammatory responses and that LMP2/Y inhibition may offer a new therapeutic strategy for neuroinflammatory diseases including AD

Methods

Results

Conclusion