代謝性症候群之極低密度脂蛋白誘發小鼠神經發炎與認知異常

Very low density lipoprotein from metabolic syndrome subject induced neuronal inflammation and cognitive dysfunction in mice

林盈劭(Ying-Shao Lin)

指導教授 ： 陳秀蘭

高雄醫學大學/醫學院/醫學研究所碩士班/碩士(2018年)

摘要

先前研究證實，代謝性症候群患者血液中的極低密度脂蛋白 (very low density lipoprotein , 簡稱 VLDL) 具較高之陰電性，並造成血管內皮細胞較大之
損傷，然而其對中樞神經的影響尚未知。我們假設長期血液中過多的陰電性 VLDL 可能會傷害中樞神經細胞，進而造成認知功能下降。 本研究以動物認知行為模式，來看不同陰電性 VLDL 對於神經功能之影 響，並分析認知功能相關腦區來探討其相關機轉。從正常受試者 (normal) 及代 謝性症候群 (metabolic syndrome, met) 患者的血液中，我們分別分離出具有較 低 (nVLDL) 與較高 (metVLDL) 陰電性的 VLDL ，以 15 μg/g BW 的劑量連 續 6 週注射於 10 個月大小鼠之尾靜脈，而其中 1 組 metVLDL 動物在最後兩 週 (6-8 週) 餵食何首烏萃取物 (EH201)。 在活動度測試上，連續注射 6 週 nVLDL 或 metVLDL 的小鼠分別在中央 及周邊區域活動度表現增加。Y 迷宮行為測試結果顯示，小鼠注射 3 週的 metVLDL 即明顯的減少對於新奇區域探索之比例，顯示有認知功能退化之情 形。連續注射 6 週的 nVLDL 或 metVLDL 後，兩組小鼠均表現明顯認知功能 退化之情形，而餵食 EH201 則可改善 metVLDL 所導致的認知退化。相關蛋白 分子研究顯示 metVLDL 組其血液 TGF-β1、皮質區 BDNF 及 Aβ42 皆顯著 增加，而餵食 EH201 可改善 metVLDL 所導致的相關蛋白質表現。另外，膠 細胞染色分析顯示，長期注射 nVLDL 及 metVLDL 皆使小鼠之前中額葉皮 質 (medial prefrontal cortex, mPFC) 與海馬迴腦區之小膠細胞表現量增加，其 中又以 metVLDL 增加最為顯著。 MetVLDL 也使海馬迴 CA1 及 CA3 腦區 的星狀膠細胞表現量明顯增加。而餵食 EH201 能減少 metVLDL 所引起的 膠細胞增生。綜合上述，不同陰電性 VLDL 誘發不同程度中樞神經發炎並影 響中年小鼠認知功能，而餵食 EH201 能改善 metVLDL 所引起的神經副作用。

關鍵字

代謝性症候群 ； 極低密度脂蛋白 ； 中樞神經發炎

並列摘要

Previous study indicated that very low density lipoprotein (VLDL) with negatively charged propriety in metabolic syndrome subjects, proven as a vascular risk factor. However, its effect to neuronal function is still unknown. We hypothesize that negative charged VLDL might damage the neuronal cells and impaired the cognitive function. The animal behavior model and related brain analysis were performed to investigate its effects and mechanism. First, we isolated the VLDL from the normal (nVLDL) and metabolic syndrome (metVLDL) subjects. Second, to verify the long-term effects of different negative charged VLDL in central nervous system. 10-month-old mice were tail vein injected with nVLDL (15 μg/g BW) or metVLDL (15 μg/g BW) for 6 weeks. Moreover, the compounds extracted from Radix Polygoni multiflori (EH201) was fed to the mice injected with metVLDL in the last two weeks (6-8 week). In locomotor activity test, long term (6 weeks) injected of nVLDL or metVLDL increased of travel distance in central or peripheral zone respectively. In Y-Maze test, metVLDL group showed early cognitive dysfunction due to a lower exploration rate of novel arm at the 3rd week. At the 6th week, both nVLDL and metVLDL groups exhibited a significant declined in novel arm exploration. Treatment with EH201 protect the metVLDL-induced cognitive impairment. In proteomic molecular analysis, long term metVLDL induced significant elevation of TGF-β1 in plasma, BDNF and Aβ42 expression in cortex. EH201 treatment improved these molecular expression induced by metVLDL. We further analyzed the degrees of glia cell expression in cognition related brain region. In both nVLDL and metVLDL groups, microglial expression significantly increased in medial prefrontal cortex (mPFC) and hippocampus. Moreover, significant increasing of astroglia in hippocampus CA3 and CA1 was found in metVLDL group. Combination of EH201 with suppressed the overexpression of glia cell in brain. Taken together, our findings suggest that long term exposure of different negative charged VLDL induced different degree of neuronal inflammation and contribute to cognitive dysfunction, combination of EH201 treatment may attenuate the impact of metVLDL.

並列關鍵字

metabolic syndrome ； VLDL ； neuronal inflammation

參考文獻

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