實驗性腦部犬蛔蟲症進展成神經退化疾病之分子機轉

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題名:	實驗性腦部犬蛔蟲症進展成神經退化疾病之分子機轉 Molecular pathogenesis of experimental cerebral toxocariasis progress into neurodegenerative diseases
作者:	周嘉玫 Chou, Chia-Mei
貢獻者:	醫學科學研究所
關鍵詞:	犬蛔蟲;神經退化;星狀膠質細胞;犬蛔蟲排泌性抗原;細胞凋亡 Toxocara canis;Neurodegeneration;Astrocyte;T. canis excretory-secretory antigens;Apoptosis
日期:	2018
上傳時間:	2019-01-03 09:36:36 (UTC+8)
摘要:	犬蛔蟲症是盛行於世界各地的人畜共通寄生蟲疾病，主要是由感染犬蛔蟲所引起。犬蛔蟲幼蟲長期入侵保幼宿主的腦部會導致腦部犬蛔蟲症，不論在人類腦部犬蛔蟲症的臨床案例或是犬蛔蟲症的實驗小鼠模式中，皆已被證實犬蛔蟲幼蟲入侵至保幼宿主腦部會誘發腦部損傷及神經性發炎，進而導致神經退化及其他神經方面的症狀。海馬迴是負責空間記憶塑形與儲存的重要腦區，然而寄生蟲的入侵可能會造成海馬迴神經性發炎並進而誘發神經退化相關疾病;星形膠質細胞是腦部含量最豐富的膠質細胞並與腦部宿主免疫反應極為相關，然而星形膠質細胞的過度活化甚至死亡已被認為是神經退化相關疾病，例如是阿茲海默症的重要相關致病因子。本研究以低、中、高劑量分別感染二十週的慢性犬蛔蟲症小鼠動物模式加以分析其學習與記憶行為能力、腦部病理變化以及神經退化相關因子與泛素－蛋白酶體系統的功能與表現；同時並以細胞培養模式探討犬蛔蟲排泌性抗原誘發星狀膠質細胞毒殺作用之相關機轉。研究結果顯示雖然在不同劑量之犬蛔蟲感染小鼠其學習與記憶能力並未因受到犬蛔蟲感染而影響，而這有可能是因為犬蛔蟲幼蟲並未入侵至小鼠的海馬迴而是入侵其周圍腦區所致；另外，在感染犬蛔蟲第八周、十六週與二十週的小鼠中發現其海馬迴有大量表現的神經退化相關因子、泛素－蛋白酶體系統的功能失調與大量堆積的β類澱粉蛋白，顯示持續性的腦部犬蛔蟲可能會進而誘發神經退化的發生。在細胞實驗中，研究結果顯示犬蛔蟲排泌性抗原會降低星形膠質細胞存活率、使細胞型態改變並伴隨顯著上升的cleaved caspase-3、caspase-8、caspase-9及cytochrome c的蛋白表現，而細胞螢光染色結果亦顯示犬蛔蟲排泌性抗原會促使星形膠質細胞caspase-3的活化與細胞凋亡；然而，細胞自噬相關促進因子Beclin 1 與 LC3-Ⅱ的蛋白表現量並未受到犬蛔蟲排泌性抗原的影響，且另一細胞自噬相關促進因子p62的蛋白表現則有顯著性下降；細胞自噬相關抑制因子mTOR的蛋白表現量亦有顯著下降，然而磷酸化的mTOR並未受到影響；這些研究結果顯示犬蛔蟲排泌性抗原可以誘發星狀膠質細胞的凋亡而非細胞自噬。總結來說，本研究顯示犬蛔蟲幼蟲入侵保幼宿主腦部後可能透過持續的誘發神經退化相關因子的大量表現、泛素－蛋白酶體系統的功能失調與β類澱粉蛋白質的大量堆積，並以其排泌性抗原誘發星狀膠質細胞凋亡，促使腦部犬蛔蟲症的發生並進而可能導致宿主神經退化的發生。 Toxocariasis is a worldwide parasitic zoonosis and mainly caused by Toxocara canis. Long-term residence of T. canis larvae in a paratenic host’s brain can cause cerebral toxocariasis (CT). In human CT and mouse model of CT, T. canis larval brain invasion can cause cerebral damage and neuroinflammation, further contributing to several neurological symptoms and neurodegenerative disorders. Hippocampus is characterized for synaptic plasticity and spatial learning and memory; however parasitic invasion of hippocampus may trigger neuroinflammatory and neurodegenerative disorders. Astrocytes are the most abundant glia cells manipulating the host’s defense in the brain; moreover, they are proposed to pathologically involve in neurodegenerative disorders, including Alzheimer’s disease. The present study intended to assess pathological changes, expressions of neurodegeneration-associated factors (NDAFs) and ubiquitin-proteasome system (UPS) function in hippocampus and associated cognitive behavior in ICR mice orally inoculated with a high, medium or low-dose of T. canis embryonated ova during a 20-week investigation. Secondly, the cytotoxic effects of T. canis larval excretory-secretory antigens (TcES Ag) on astrocytes were assessed by apoptosis and autophagy expressions in vitro. Our results indicated there were insignificant differences in learning and memory function between the experimental and uninfected control mice, possibly because the site where T. canis larvae invaded was the surrounding area but not the hippocampus per se. Nevertheless, enhanced expressions of NDAF, persistent UPS impairment and excess amyloid β (Aβ) accumulation concomitantly emerged in the experimental mice hippocampus at 8, 16 and 20 weeks post-infection. In addition, TcES Ag treatment reduced cell viability and caused morphological changes. Expressions of autophagy associated proteins including Beclin 1, phosphor-mTOR and LC3-Ⅱ were not significantly changed; however, p62 as well as the cell survival protein, mTOR, was concomitantly decreased in TcES Ag treatment. Significantly accelerated cleaved caspase-3 and cytochrome c expression as well as enhanced caspase-9 and caspase-8 activation were found in astrocytes with TcES Ag treatment. Caspase-3 activity and apoptotic cells numbers were also increased as detected by fluorescence microscopy, implying that TcES Ag may trigger astrocytes apoptosis predominantly through intrinsic and extrinsic pathways rather autophagy to further contribute to the disease progression of CT. This study provides a comprehensive role in the pathogenesis of CT progress into neurodegenerative diseases.
描述:	博士指導教授：范家堃
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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