USP53 promotes NOTCH2-induced neuroinflammation in Alzheimer's disease.

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.