Modulation of IKKβ deubiquitination dynamics by CYLD links microglia-neuron crosstalk to be involved in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder with limited therapeutic options. Microglia-mediated neuroinflammation plays a critical role in its pathogenesis. Depending on the microenvironment, activated microglia can adopt either a pro-inflammatory or an anti-inflammatory phenotype. Previous studies have shown that ablating the microglial inhibitor of NF-κB kinase subunit β (IKKβ) suppresses inflammatory activation and beta-amyloid (Aβ) accumulation, yet the underlying mechanism remains unclear. In this study, we found that IKKβ expression was significantly upregulated, whereas its ubiquitination level was markedly reduced in AD mouse models. Cylindromatosis (CYLD) was identified as a deubiquitinase that removes both K48- and K63-linked polyubiquitin chains from IKKβ. Knockdown of CYLD decreased IKKβ expression, dampened pro-inflammatory cytokine secretion, and attenuated neuronal apoptosis, ultimately leading to improved cognitive function in AD mice. Mechanistically, CYLD ablation enhanced IKKβ ubiquitination, attenuated NF-κB signaling, and promoted tissue-repair-associated microglial polarization. Consistently, direct microglial knockout of IKKβ repressed NLRP3 inflammasome activation and pro-inflammatory cytokine production, which in turn restrained neuronal pyroptosis. Collectively, our findings establish that microglial IKKβ plays an essential role in neuroinflammation during AD progression, and suggest that targeting IKKβ deubiquitination in microglia may represent a novel therapeutic strategy for AD.