Targeting UAF1 Alleviate Neurotoxicity by Inhibiting APP/NLRP3 Axis-Mediated Pyroptosis and Apoptosis

The accumulation of amyloid β (Aβ) protein, derived from the amyloid precursor protein (APP), plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) by inducing neuronal cell injury. This study investigated the specific functions of ubiquitin-specific protease 1-associated factor 1 (UAF1) in mediating the neurotoxic effects triggered on Aβ. To model AD-related neuronal injury in vitro and in vitro, SH-SY5Y cells exposed to Aβ_25-35 and APPswe/PS1dE9 (APP/PS1) transgenic mice were utilized. Compared with control mice, UAF1 levels were significantly elevated in the hippocampus of experimental mice. In vitro experiments showed that UAF1 knockdown reduced Aβ-induced apoptosis and enhanced cell viability. Furthermore, UAF1 knockdown markedly suppressed Aβ_25-35 -induced pyroptosis in SH-SY5Y cells and reduced the production of IL-1β and IL-18 through the nucleotide-binding domain and leucine-rich repeat containing family pyrin domain-containing 3 (NLRP3)/Gasdermin D pathway. Mechanistic analyses revealed that UAF1 directly binds to NLRP3 to mediate its effects. In vivo, UAF1 knockdown mitigated cognitive deficits, decreased APP expression, Aβ plaque deposition, and reduced hyperphosphorylated Tau levels. These findings underscore the critical role of UAF1 in regulating neuronal apoptosis and pyroptosis, thereby highlighting its potential as a promising therapeutic target for AD.