A novel therapeutic target of the amyloid-beta neurotoxicity in Alzheimer's disease : (E2-25K/Hip-2 as an upstream of caspase-12 and stress pathway)

다국어 초록 (Multilingual Abstract)

Accumulation of amyloid-β peptide(Aβ) and its neurotoxicity are regarded as a major factor promoting neuronal degeneration in Alzheimer's disease(AD). Upon investigation of Aβ toxicity using DNA microarray, we isolated an ubiquitin conjugating enzyme E2-25K/Hip-2 as a novel mediator of Aβ toxicity. Here we show that the expression of E2-25K/Hip-2 was strongly up-regulated in the cultured cortical neurons exposed to Aβ_(1-42) in vitro and in vulnerable neurons surrounding senile plaques of the brains derived from AD patients and Tg2576 Alzheimer's mice. Aβ_(1-42)-induced neurotoxicity, accumulation of ubiquitin conjugates, and decrease of the proteasome activity were mediated by ubiquitin ligase activity of E2-25K/Hip-2. Aβ_(1-42)-induced accumulation and activation of caspase-12 were regulated by E2-25K/Hip-2. The E2-25K/Hip-2-induced cell death was attenuated by expression of the dominant negative caspase-12 and caspase-12(-/-) EF cells. Ubiquitin mutant, UBB+1 found in Alzheimer's patients was co-localized with E2-25K/Hip-2 in the brain of Alzheimer's patients and functionally coordinated with E2-25K/Hip-2 for its neurotoxicity. These results suggest that E2-25K/Hip-2 is an important factor coordinating Aβ toxicity in vulnerable neurons via ubiquitin/proteasome-caspase-12 circuit, leading to neuronal damage in the brain of AD patient.