Immunoproteasome Subunit Low Molecular Mass Peptide 2 (LMP2) Deficiency Ameliorates LPS/Aβ-Induced Neuroinflammation.

Low molecular mass peptide 2 (LMP2) is the β1i subunit of immunoproteasome (iP) which plays a key role in neuroinflammatory responses, and inhibition of iP exhibits a high neuroprotective action against neurodegenerative diseases. Since neuroinflammation has been shown to be involved in the development and progression of Alzheimer's disease (AD), the aim of this study was to evaluate the anti-inflammatory role of LMP2 deficiency in AD in vivo and in vitro. Here, we found that LMP2 was upregulated in the brains of 5 × FAD and APP/PS1 mice and increased with age in C57/BL6 mice. We showed that the lack of LMP2 significantly decreased NLRP3 expression and downstream cytokine release in microglia, resulting in partially blocking Aβ- or LPS-induced inflammation in vivo and in vitro, which ameliorated cognitive deficits in aged rats and D-galactose + Aβ-treated rats. These results suggest that LMP2 contributes to the regulation of LPS-or Aβ-driven innate immune responses by diminishing NLRP3 expression and clarify that inhibition of iP function may mediate the inflammatory-related cognitive phenotype.