Summary Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with limited therapeutic options. Here, we report that tuberostemonine (Tub), an alkaloid from Stemona tuberosa, exerts neuroprotective effects in AD models. In Aβ1-42-treated PC12 cells, Tub reduced cytotoxicity, apoptosis, and oxidative stress while restoring mitochondrial function. In APP/PS1 transgenic mice, Tub administration improved cognitive performance, reduced amyloid-β plaque deposition, attenuated microglial activation, and attenuated neuronal loss, with efficacy superior to donepezil. Mechanistically, Tub selectively inhibited p38 MAPK phosphorylation without affecting ERK or JNK pathways, as confirmed by pharmacological inhibition and activation experiments. These findings identify Tub as a promising multi-target natural compound for AD intervention through p38 MAPK pathway modulation.
ABSTRACT Neuroinflammation driven by microglial activation is a defining feature of Alzheimer's disease (AD), yet the molecular mechanisms sustaining this proinflammatory state remain unclear. Here, we identify the deubiquitinase OTUD7B as a critical regulator of microglial activation and AD pathology. OTUD7B expression was markedly elevated in microglia from AD mouse models and human patient datasets. Genetic ablation of OTUD7B markedly attenuated microglial activation and cytokine release, alleviated neuronal injury, and improved cognitive performance in AD mice. Mechanistically, OTUD7B directly interacted with STAT3 and removed K48‐linked ubiquitin chains at lysine 283, thereby stabilizing STAT3, promoting its nuclear translocation, and enhancing transcription of proinflammatory mediators. Integrative transcriptomic analysis revealed that OTUD7B deficiency suppressed proinflammatory transcriptional programs in microglia. Together, these findings uncover an OTUD7B‐STAT3 signaling axis that sustains microglial‐driven neuroinflammation and identify OTUD7B as a potential therapeutic target for mitigating neurodegenerative pathology in AD.
Luyao Li, Hao Tang, Qin Yu et al.· Advancement of science· 0 citations
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