沈賜川吳瑞碧鄭勤巧TEE QIN QIAO2019-08-282019-8-252019-08-282014http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=id=%22GN060106071E%22.&%22.id.&http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/86915高脂飲食易促使肥胖、周邊胰島素阻抗及糖尿病等疾病進程，接續造成腦部胰島素阻抗而最終導致阿茲海默症(Alzheimer’s disease, AD)的發生。流行病學研究顯示，第二型糖尿病病患罹患阿茲海默症的機率較正常人高出兩到三倍。本實驗室先前以胰島素阻抗細胞模式篩選出本實驗樣品--咖啡酸(caffeic acid)，且在動物實驗中發現其具有改善腦部醣類代謝及胰島素訊息傳遞的效果。因此，本研究進一步探討咖啡酸可否預防以高脂飲食(脂質佔總熱量60%)誘導高胰島素血症大鼠阿茲海默症的發生，並釐清其機制。 水迷宮試驗結果顯示，合併管餵咖啡酸(30mg/ kg b.w.) 30週後可顯著改善高胰島素血症大鼠的學習及記憶能力；在抗氧化系統中，咖啡酸可預防高脂飲食所造成的海馬迴及大腦皮質超氧岐化酶 (superoxide dismutase, SOD) 失活，並可增加大腦皮質麩胱甘肽 (glutathione) 捕捉自由基的能力；以西方點墨法分析發現，咖啡酸可增加高胰島素血症大鼠海馬迴胰島素訊息傳遞下游路徑蛋白：蛋白激酶B (p-AKT/PKB)、磷酸化肝醣合成酶 (phospho-glycogen synthase 3β, p-GSK3β) 的表現量，以降低tau蛋白的過度磷酸化。此外，咖啡酸可降低海馬迴類澱粉蛋白前驅物 (amyloid protein precursor, APP)及APP β部位切割酵素 (β-site APP cleaving enzyme, BACE) 的表現量，進而減少海馬迴中類澱粉蛋白1-42 (β-amyloid 1-42, Aβ 1-42) 的堆積。在大腦皮質部分，咖啡酸可提高具有神經保護功效的腦源性神經滋養因子 (brain-derived neurotrophic factor, BDNF) 及突觸相關蛋白的表現，且有助於降低胰島素降解酵素 (insulin degrading enzyme, IDE) 因代償作用的過量表現。 由以上結果推測，咖啡酸可透過改善胰島素/瘦體素訊息傳遞、降低神經細胞氧化壓力、減少tau蛋白過度磷酸化、阻斷類澱粉蛋白生成及增加神經滋養因子等神經保護機制，以有效預防阿茲海默症的發生。High fat-diet (HFD) promotes obesity, increases the risk of insulin resistance and diabetes mellitus (DM). It also contributes to brain insulin resistance and the pathogenesis of Alzheimer’s disease (AD). Epidemiologically, patients with Type 2 DM have a two-to three-fold increased risk for AD. We previously confirmed caffeic acid improves glucose metabolism and alleviates insulin resistance in cell and animal models. In this study, we further investigate the alleviative effect of caffeic acid on AD pathogenesis and associated mechanisms in HFD (60% fat) induced hyperinsulinemic rats. According to the results of Morris water maze, caffeic acid (30mg/ kg b.w./ day) significantly ameliorated memory and learning impairment in hyperinsulinemic rats. Caffeic acid enhanced superoxide dismutase (SOD) activity and the glutathione free radical scavenger activity in hyperinsulinemic rats. The results from western blotting shows that protein expressions of p-AKT/Protein kinase B (p-AKT/ PKB), p-glycogen synthase kinase3β (p-GSK3β) significantly increased, whereas, the expression of p-tau decreased in hippocampus of rats administered with caffeic acid compared with the hyperinsulinemic control group. Besides, the expression of amyloid precursor protein (APP) and β-site APP cleaving enzyme (BACE) were attenuated in the hippocampus of hyperinsulinemic rats treated with caffeic acid, therefore lowered the level of β-amyloid 1-42(Aβ 1-42). Experimentally, caffeic acid increased the expressions of brain-derived neurotrophic factor (BDNF) and synaptic protein in the cortex compared with the hyperinsulinemic control group. Compensatory effect of insulin degrading ezyme (IDE) in hyperinsulinemic rats was also reduced by the administration of caffeic acid. Above observation suggests that caffeic acid may exhibit the neuroprotective effect via improves insulin/leptin signaling, decreases oxidative stress, attenuates the hyperphosphorylation of tau protein and amyloidgenic pathway, and upregulates the expression of neurotrophic factor, thus may prevent the pathogenesis of AD.咖啡酸高胰島素血症阿茲海默症caffeic acidhyperinsulinemicAlzheimer's disease