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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / enzymology
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Alzheimer Disease / genetics
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism
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Animals
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Brain / drug effects*
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Brain / enzymology
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Brain / pathology
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Cell Line
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Cognitive Dysfunction / drug therapy*
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Cognitive Dysfunction / enzymology
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Cognitive Dysfunction / genetics
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Cognitive Dysfunction / pathology
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Cysteine Endopeptidases / genetics*
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Cysteine Endopeptidases / metabolism
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Disease Models, Animal
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Gene Expression Regulation
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Humans
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Interleukin-1alpha / genetics
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Interleukin-1alpha / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Liver / drug effects
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Liver / enzymology
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Liver / pathology
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Maze Learning / drug effects
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Mice
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Mice, Inbred ICR
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Mice, Transgenic
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Monocyte Chemoattractant Proteins / genetics
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Monocyte Chemoattractant Proteins / metabolism
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Neuroglia / drug effects*
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Neuroglia / enzymology
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Neuroglia / pathology
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Proteasome Inhibitors / pharmacology*
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Protein Subunits / antagonists & inhibitors
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Spleen / drug effects
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Spleen / enzymology
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Spleen / pathology
Substances
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Amyloid beta-Peptides
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Ccl12 protein, mouse
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Il1a protein, mouse
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Interleukin-1alpha
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Interleukin-6
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Monocyte Chemoattractant Proteins
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Proteasome Inhibitors
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Protein Subunits
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interleukin-6, mouse
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LMP-2 protein
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Cysteine Endopeptidases