Microglial OTUD6A promotes neuroinflammation and Alzheimer's disease pathogenesis by deubiquitinating C/EBPβ

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, neuroinflammation, and cognitive decline. Microglia, the brain's primary immune cells, play a central role in AD pathogenesis by driving neuroinflammatory responses. Deubiquitinating enzymes (DUBs) regulate microglial activation, but the role of the ovarian tumor domain-containing DUB OTUD6A in AD remains unclear. In this study, we demonstrate that OTUD6A is upregulated in microglia across multiple AD models, including Aβ-infused mice, 3 ×Tg mice, and APP/PS1 mice. Otud6a KO or microglia-specific knockdown Otud6a ameliorated cognitive deficits and reduced neuroinflammation in AD mice. Besides, OTUD6A binds to C/EBPβ by removing K48-linked ubiquitin chains at lysine 253 (K253), thereby leading to C/EBPβ accumulation and enhancing NF-κB signaling and proinflammatory cytokine production. Moreover, mutation of OTUD6A catalytic residue (C157A) abolished its deubiquitination activity, confirming its role in C/EBPβ stabilization. Furthermore, C/EBPβ knockdown reversed OTUD6A-mediated neuroinflammation, validating the microglial OTUD6A-C/EBPβ-NF-κB axis as a critical pathway in AD pathogenesis. Therefore, our findings highlight OTUD6A as a novel regulator of microglial activation and suggest that targeting this DUB could provide a therapeutic strategy to mitigate neuroinflammation in AD.