2022-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/708233阿茲海默症（AD）是一種神經退化性疾病，致病機轉近年被認為和中樞以及周邊神經系統的發炎反應(neuroinflammation)有關。另一方面，牙周病亦是一種細菌感染導致發炎的疾病。至今雖已有愈來愈多流行病學研究支持牙周病和AD之間的關聯性，但對於兩疾病之間的致病機轉，尚不明暸。雖然最新的研究指出，在大腦發現的牙周病病菌Porphyromonas gingivalis (P. gingivalis)可能將這兩種發炎退行性疾病聯繫在一起，然目前尚未有研究報導P. gingivalis 分泌帶有內毒素脂多醣(lipopolysaccharide, LPS) 之 OMVs是否經由endocytosis等機制，誘發非典型發炎小體路徑(Non-canonical inflammasome pathway)造成中樞神經細胞焦亡(Pyroptosis)、及誘發典型發炎小體路徑 (canonical inflammasome pathway)造成inflammasome complex 的產生，繼而促進大腦β-澱粉樣蛋白的形成。本實驗室是第一個由P. gingivalis標準株(ATCC33277)成功分離出牙周病外膜囊泡毒素(P. gingivalis OMVs) 的團隊，在此二年期的研究計畫，第一部分以細胞實驗探討P. gingivalis OMVs是否誘導神經細胞產生發炎小體(Inflammasome)以及造成中樞神經細胞焦亡，包含neuronal cells。第二部分觀察P. gingivalis OMVs是否會抑制神經膠細胞清除β-澱粉樣蛋白，進而造成神經膠細胞死亡。第三部分建構AD transgenic mice (APP PS1), 以動物實驗證明P. gingivalis OMVs加速大腦濤蛋白和β-澱粉樣蛋白的堆積，並誘發小鼠認知行為退化。此計畫有助於探討牙周病致病菌(pathogenic bacteria) 在AD 發病機制(pathogenesis)所扮演的角色。 Alzheimer`s disease (AD) is a neurodegenerative disease driven by pathogenesis that involves central and peripheral nervous system inflammation. On the other hand, periodontal disease is an inflammatory disease downstream to bacterial infections. Although epidemiological studies have established the association between periodontal disease and Alzheimer’s disease, the underlying pathogenic mechanism is still unknown. Latest research has proposed that the periodontal pathogen, Porphyromonas gingivalis (P. gingivalis), has been identified in brain biopsies of AD patients, which supports the link between these two inflammatory degenerative diseases. Our team is the first to successfully isolate P. gingivalis outer membrane vesicle (P. gingivalis OMVs) from the standard strain of P. gingivalis (ATCC33277). To date, there is no research reporting whether P. gingivalis OMVs may (1) induce non-canonical inflammasome pathway through endocytosis, or may (2) stimulate the formation of inflammasome complex in canonical inflammasome pathway, which would cause neuronal cell pyroptosis, and further promote β-amyloid protein accumulation in the brain. The first part of this two-year research project is to investigate whether P. gingivalis OMVs may induce inflammasome production in neuronal cells and cause pyroptosis of these neurons. The second part is to observe whether P. gingivalis OMVs may inhibit glial cells from clearing β-amyloid, and then cause glial cell death. The third part is animal experiment. AD transgenic APP PS1 mice will be used to study how P. gingivalis OMVs accelerate the accumulation of cerebral tau-protein and β-amyloid, and induce cognitive behavior degradation in mice. Overall, the results of this project will improve our understanding of the role of periodontal bacterial toxins in AD pathogenesis.阿茲海默症牙周病澱粉樣斑塊發炎小體細胞焦亡Alzheimer`s diseaseperiodontal diseaseβ-amyloid plaquesinflammasomepyroptosis