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.
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We would like to thank the National Institutes of Health (R01 CA188354 to K.B.K.), National Research Foundation of Korea (2018R1D1A1A02086334 to A.B. and MRC2017R A5A2015541 to J.T.H), and the National Research Council of Science & Technology (NST) granted by the Ministry of Science, ICT & Future Planning (MSIP) (No. CRC-15-04-KIST to Y.K.K.) for financially supporting this work.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Yeo, In Jun; Lee, Min Jae; Baek, Ahruem; Miller, Zachary; Bhattarai, Deepak; Baek, Yu Mi; Jeong, Hyun Jung; Kim, Yun Kyung; Kim, Dong-Eun; Hong, Jin Tae; and Kim, Kyung Bo, "A Dual Inhibitor of the Proteasome Catalytic Subunits LMP2 and Y Attenuates Disease Progression in Mouse Models of Alzheimer's Disease" (2019). Pharmaceutical Sciences Faculty Publications. 153.