Amyloid-beta Degradation and Neuroprotection of Dauricine Mediated by Unfolded Protein Response in a Caenorhabditis elegans Model of Alzheimer's disease

Abstract

Amyloid plaque is a prominent pathologic hallmark in the brains of patients with Alzheimer's disease (AD), and it has been shown to be associated with endoplasmic reticulum (ER) stress response. However the precise regulation mechanism of amyloid-beta (Aβ) toxicity remains unclear. Here, we found that dauricine could activate X-box binding protein 1 (XBP-1; active form XBP-1S) and eukaryotic translation initiation factor eIF2α and thus delay the progression of AD in the Aβ_1-42-transgenic Caenorhabditis elegans CL2120. The ER stress response factor XBP-1 can be activated and shows neuroprotective activity through acceleration of Aβ clearance. Our study reveals that dauricine activates the ire-1/xbp-1 and perk/eIF2α pathways of the unfolded protein response, attenuates translation, and enhances ER-associated degradation, which reduces Aβ expression and attenuates Aβ-associated toxicity. On the contrary, xbp-1 depletion counteracts the effects of dauricine on Aβ-associated toxicity. These results underscore the functional relevance of XBP-1 in Aβ toxicity and degradation, and highlight the potentially pharmacodynamic value of dauricine in preventing the progression of AD.

Keywords: Alzheimer’s disease; Aβ; ER-associated degradation; dauricine; unfolded protein response.