FBXW11 deletion alleviates Alzheimer's disease by reducing neuroinflammation and amyloid-beta plaque formation via repression of ASK1 signaling

文献类型： 外文期刊

第一作者： Sun, Jingjie

作者： Sun, Jingjie;Zhang, Xinyan;Wang, Qi;Zhang, Wei;Wang, Manxia;Qin, Xiaodong

作者机构：

关键词： Alzheimer's disease (AD); FBXW11; Neuroinflammation; ASK1; NF-kappa B and MAPKs

期刊名称：BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS （ 影响因子：2.985； 五年影响因子：2.75 ）

ISSN： 0006-291X

年卷期： 2021 年 548 卷

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收录情况： SCI

摘要： Y Alzheimer's disease (AD) is a neurodegenerative disease with a complicated pathogenesis. F-box and WD-40 domain protein 11 (FBXW11), as a component of the SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase complex, regulates multiple different signaling pathways. However, the effects of FBXW11 on AD progression and the underlying mechanisms have not been studied. In this study, we found that FBXW11 expression was markedly increased in microglial cells stimulated by amyloid-beta (A beta). Immunofluorescence staining showed that FBXW11 was co-localized with Iba-1 in microglial cells, suggesting its potential in regulating neuroinflammation. Meanwhile, significantly elevated expression of FBXW11 was detected in hippocampus of AD mouse models. Then, our in vitro studies showed that FBXW11 deletion considerably ameliorated inflammatory response in Ab-incubated microglial cells through suppressing nuclear transcription factor kappa B (NF-kappa B) signaling. We further found that FBXW11 physically interacted with apoptosis signal-regulating kinase 1 (ASK1) and promoted its ubiquitination, which led to the aberrant activation of NF-kappa B and mitogen-activated protein kinase (MAPK) signaling pathways. Importantly, promoting ASK1 significantly abolished the effects of FBXW11 knockdown to repress inflammation and MAPKs/NF-kappa B activation in Ab-treated microglial cells. Subsequently, our in vivo experiments demonstrated that hippocampus-specific knockout of FBXW11 dramatically alleviated Ab plaque load, neuronal death, and microglial activation in AD mice. Furthermore, hippocampal deficiency of FBXW11 markedly mitigated neuroinflammation in AD mice through restraining ASK1/MAPKs/NF-kappa B signaling, along with alleviated cognitive deficits. Together, our findings demonstrated that FBXW11 may be a functionally important mediator of ASK1 activation, which could be a novel molecular target for AD treatment. (C) 2020 Published by Elsevier Inc.

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