Neurochemistry international · 2025
USP53 promotes NOTCH2-induced neuroinflammation in Alzheimer's disease.
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He Dandan, Zhao Huajian, Zhu Yong, Kou Yufei, Liu Tao, Huang Huahai, Yang Haiming, Zhang Lihua, Deng Jingyue, Xu Feng, Wang Qingyong
Аннотация
PURPOSE: This study aimed to investigate the role of USP53 and its associated signaling pathway associated with USP53 in Alzheimer's disease (AD).
METHODS: In vivo experiments were conducted in C57BL/6, 5XFAD, and USP53-knockout 5XFAD (USP53-/-) mice. In vitro experiments were performed using primary human microglia cells. mRNA expression was examined using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Protein expression was measured using western blotting and immunofluorescence (IF). Immunoprecipitation (Co-IP) was used to detect protein-protein interactions. Morris Water Maze (MWM) was used to evaluate the learning ability and memory of mice.
RESULTS: USP53 was overexpressed in patients with AD. Knockout of USP53 downregulated the expression of CD68, glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1) and neuronal nuclear protein (NeuN), as well as the inflammatory mediators, interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). The accumulation of Tau protein was reduced, and the learning ability and memory was improved in USP53-/- mice compared to 5XFAD mice. In vitro experiments demonstrated that protein-protein interaction existed between USP53 and NOTCH2 and that the inhibition of USP53 prevented amyloid-beta (Aβ)-induced deubiquitination of NOTCH2. Knockdown of USP53 reduced Aβ-induced elevation of inflammatory mediators and repressed Aβ-induced activation of IKKβ/NFκB signaling pathway in microglia.
CONCLUSION: USP53 promotes the activation of neuroinflammation and worsens learning ability and memory in AD mice, mediated by NOTCH2.
METHODS: In vivo experiments were conducted in C57BL/6, 5XFAD, and USP53-knockout 5XFAD (USP53-/-) mice. In vitro experiments were performed using primary human microglia cells. mRNA expression was examined using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Protein expression was measured using western blotting and immunofluorescence (IF). Immunoprecipitation (Co-IP) was used to detect protein-protein interactions. Morris Water Maze (MWM) was used to evaluate the learning ability and memory of mice.
RESULTS: USP53 was overexpressed in patients with AD. Knockout of USP53 downregulated the expression of CD68, glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1) and neuronal nuclear protein (NeuN), as well as the inflammatory mediators, interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). The accumulation of Tau protein was reduced, and the learning ability and memory was improved in USP53-/- mice compared to 5XFAD mice. In vitro experiments demonstrated that protein-protein interaction existed between USP53 and NOTCH2 and that the inhibition of USP53 prevented amyloid-beta (Aβ)-induced deubiquitination of NOTCH2. Knockdown of USP53 reduced Aβ-induced elevation of inflammatory mediators and repressed Aβ-induced activation of IKKβ/NFκB signaling pathway in microglia.
CONCLUSION: USP53 promotes the activation of neuroinflammation and worsens learning ability and memory in AD mice, mediated by NOTCH2.