Icariin improves learning and memory function by enhancing HRD1-mediated ubiquitination of amyloid precursor protein in APP/PS1 mice

Background One of the hallmark pathological characteristics of Alzheimer's disease (AD) is amyloid-β (Aβ) accumulated in brain, which is mainly derived from the proteolytic processing of amyloid-β protein precursor (AβPP). The ubiquitin-proteasome system is able to reduce Aβ generation by ubiquitination and degradation of AβPP. Icariin (ICA), a flavonoid isolated from Epimedium brevicornum Maxim., has been reported that it could regulate the metabolism of AβPP and reduce the Aβ level in AD in vivo and in vitro models. Objective To investigate whether the effect of ICA on AβPP and Aβ is related to AβPP ubiquitination. Methods We used in vivo and in vitro models to observe the effect of ICA on AβPP ubiquitination as well as to investigate the effect of HMG-CoA reductase degradation protein 1 (HRD1), an E3 ubiquitin-protein ligase, on the processing of AβPP ubiquitination. Results This study showed that ICA improved the cognitive abilities of APP/PS1 AD mice in Morris Water Maze and Y-maze tests, upregulated HRD1 expression, subsequently elevated the total ubiquitination and K48-linked polyubiquitination of AβPP level, as well as increased AβPP degradation. Moreover, silenced HRD1 gene abolished the aforementioned effects of ICA. Furthermore, ICA decreased the location of AβPP in the early endosome, where AβPP is cleaved into Aβ, evidenced by reducing the co-localization of AβPP and early endosome antigen 1 (EEA1). Conclusions This study demonstrated that ICA increased AβPP degradation by upregulating HRD1 mediated ubiquitination.