A novel mediator of the amyloid-βneurotoxicity in Alzheimerls disease:Ubiquitin conjugating enzyme E2-25K/Hip-2 as upstream of caspase-12

摘要

Accumulation of amyloid-β(Aβ) and its neurotoxicity are regarded as a major factor promoting neu-ronal degeneration in Alzheimer's disease (AD). Upon investigation of Aβtoxicity using DNA microarray, we isolated ubiquitin conjugating enzyme E2-25K/Hip-2 as a mediator of Aβ toxicity. Here we show that expression of E2-25K/Hip-2 was strongly up-regulated in the cultured cortical neurons exposed to Aβ1-42 in vitro and in vulnerable neurons surrounding senile plaques of the brain derived from AD patients and Tg2576 Alzheimer's mice. Aβ1-42-induced neurotoxicity, accumulation of ubiquitin conjugates, and decrease of the proteasome activity were mediated by ubiquitin ligase activity of E2-25K/Hip-2. Aβ-induced