12 カフェオイルキナ酸のアミロイドβ凝集阻害活性及び分子機構(口頭発表の部)

抄録

Amyloid β3 (Aβ) aggregation has been associated with the neurodegenerative pathology and a cascade of harmful event related to Alzheimer's disease (AD). Inhibition of Aβ aggregation and attenuation of the AP-induced cytotoxicity could be valuable therapeutics of patients with AD. Our previous study showed that 3,5-di-O-caffeoylquinic acid (3,5-di-CQA) and 3,4,5-tri-O-caffeoylquinic acid (3,4,5-tri-CQA) had a neuroprotective effect against amyloid-β_<1_42> (Aβ42)-induced apoptosis on cell death through the overexpression of glycolysis enzymes. We also found 3,5-di-CQA induced the improvement of spatial learning and memory on senescence accelerated prone mice (SAMP8). In this study, we report the inhibitory effect of CQA on Aβ42 aggregation and its cellular toxicity. Using thioflavin T assay and transmission electron microscope (TEM), 4,5-di-CQA and 3,4,5-tri-CQA inhibited the aggregation of Aβ42 in a dose-dependent manner. Structure-activity relationship of CQA and its derivatives suggest that caffeoyl group and phenolic hydroxyl group are essential for the inhibitory activity especially in a number-dependent manner of the caffeoyl groups. CQA inhibited the transformation into (β-sheet in Aβ42 and the cytotoxicity of Aβ42 on human neuroblastoma SH-SY5Y. On the other hand, CQA did not accelerate the generation of Aβ42 trimer. These results suggest that CQA could induce the formation of non-toxic conformer of Aβ42 characterized with turn at positions 25 and 26 and reduce neurotoxicity on cells by CQA treatment. CQA might be a promising agent for the prevention of AD.