알츠하이머씨 병 모델 형질전환 생쥐에서 히스톤 탈아세틸화 저해제의 효과에 관한 연구

Abstract

AD, the most common neurodegenerative disease, is characterized by the presence of neurofibrillary tangles, neuritic plaque and Aβ deposition. The AD model, Tg6799 transgenic mice, overexpress mutant human APP (695) with the Swedish (K670N, M671L), Florida (I716L) and London (V717I) mutations and mutant human PS1 (M146L and L286V). To determine biochemical changes in AD by age, the blood and brain samples were isolated from Tg6799 mice for RT-PCR and Western blot analysis. Three different age groups of 1, 5 and 10 months of age were tested for pre-symptomatic, early symptomatic, and late symptomatic stages for the study of progressive pathology of AD. The mRNA levels of IL-1β increased in plasma of Tg6799 mice at pre-symptomatic stage. The mRNA levels of NF-kB increased while the mRNA levels of TLR4 decreased in plasma of Tg6799 mice at 5 months of age, compared to littermate control. In the hippocampus of Tg6799 mice, the mRNA levels of IL-1β, APOE increased in hippocampus of Tg6799 mice at 10 months of age, compared to littermate control. The expression level of full size APP protein increased in hippocampus of Tg6799 mice at 1 month and 10 months of age. These data suggests the potential future application for early biomarker of AD.. To determine the effect of HDAC inhibitor in AD, Tg6799 mice were administered with VPA. VPA decreased the mRNA level of APOE in plasma of Tg6799 mice at 5 months of age. In the hippocampus of Tg6799 mice, VPA decreased the mRNA levels of IL-1ß and APOE at 10 months of age. In addition, VPA decreased escape latency in Morris Water Maze assessment indicating that VPA can improve an impaired memory. VPA improved spatial memory in Tg6799 mice at 5 months and 10 months of age. Since VPA decreased the mRNA levels of IL-1ß and APOE in blood and hippocampus, and improved spatial memory loss in AD, these data suggest that histone modification is one of the major key mechanism in AD pathology and so that VPA can be applied for future therapeutics of AD.