| 摘要: | 路易氏體失智症(Dementia with Lewy bodies, DLB)為神經退化性失智症中第二常見的失智症，僅次於阿茲海默氏症(Alzheimer’s disease, AD)，事實上DLB綜合了AD以及帕金森氏症(Parkinson's disease, PD)之共同的病理特徵，包括α-synuclein和β-類澱粉蛋白(Aβ)，這些錯誤摺疊蛋白在腦部大量堆積，進而造成大量的神經元損傷並造成腦部產生萎縮的現象，最終導致所對應的神經功能損傷，然而目前臨床上並無針對改善DLB的治療藥物，亟待開發新型治療策略的藥物。先前研究顯示糖尿病患者罹患失智症的機率會比一般人高出6成，而近年來也有許多研究指出新陳代謝與大腦認知功能障礙的關係是雙向的，其中胰島素訊息發生阻抗似乎是老年性神經退化的共同特徵，而腸泌素(Glucagon-like peptide-1, GLP-1)被認為可以改善胰島素發生阻抗，因此我們認為可能可以作為應用在DLB的治療策略。本研究利用條件式的方式促使α-synuclein過度表現，並且在對此細胞處理Aβ來模擬DLB患者腦部的情況，並藉由此細胞模型來探討可能造成DLB的病理機制;此外我們也建立了DLB大鼠的動物模式，並給予糖尿病臨床用藥GLP-1類似物Liraglutide探討是否可以改善DLB相關的行為症狀。結果發現Aβ確實會顯著誘發α-synuclein的細胞毒性，相對的給予Liraglutide則能有顯著提升細胞存活率，並可透過抑制pSer307-Insulin receptor substrate 1 (IRS-1)的蛋白表現來活化AKT訊息，以緩解Aβ加成α-synuclein神經毒性所導致的胰島素阻抗。此外Liraglutide亦可透過活化AMP-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR)路徑來增加自噬作用相關蛋白表現，並可以經由刺激nuclear factor erythroid 2-relaated factor2 (Nrf2)、superoxide dismutase 1 (SOD1)及Silent information regulator-mammalian ortholog 1 (Sirt1)的活性來減緩Aβ加成α-synuclein神經毒性所誘導的氧化壓力傷害。而動物實驗結果顯示給予注射Liraglutide的DLB大鼠在T型迷宮、物件辨識及憂鬱行為試驗，其工作記憶及認知功能包含憂鬱表現，比疾病組皆有明顯的改善。本研究透過細胞實驗及動物實驗證實Liraglutide可以改善Aβ加成α-synuclein神經毒性的保護效果，提供了DLB未來可能的治療策略。
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia only to Alzheimer's disease (AD). In fact, DLB shares common pathological features with AD and Parkinson's disease (PD), that simultaneously accompany α-synuclein and Aβ. These misfolded proteins accumulate in the brain and result in a large number of neuronal damage and brain atrophy, eventually leading to of the damages of the corresponding neurological function. However, there is currently no clinical treatment of drugs for the improvement of DLB. It is in urgent need for developing new therapeutic strategies of DLB drugs. According to previous studies, the risk of dementia in diabetics is 60% higher than that of the normal control. In addition, many researches have pointed out that the relationship between metabolism and cognitive impairment is bidirectional. Particularly, the resistance of insulin signals appears to be the common feature of such senile neurodegenerative diseases. Since glucagon-like peptide-1 (GLP-1) is known to improve insulin signaling, we postulate that GLP-1 may be potentially used as a treatment strategy in DLB. In. the present study, we developed a conditional approach to stimulate α-synuclein overexpression, and then treated Aβ in this cell model to mimic the pathological condition of DLB. By using this in vitro model, we explored the putative molecular mechanisms that may cause DLB. In addition, we also established a rat's DLB animal model, and investigated whether Liraglutide could improve behavioral symptoms of DLB. The results showed that Aβ significantly induced cytotoxicity of α-synuclein, whereas administration of Liraglutide significantly increased cell viability and inhibited the expression of pSer307-Insulin receptor substrate 1 (IRS-1) to activate AKT signaling. This indicates Liraglutide can alleviate insulin resistance caused by Aβ-induced α-synuclein neurotoxicity. Moreover, Liraglutide can increase autophagy-related protein expression by activating the AMP-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) pathway, which stimulate nuclear factor erythroid 2-relaated factor2 (Nrf2), superoxide dismutase 1 (SOD1) and silent information regulator-mammalian ortholog 1 (Sirt1) to reduce the oxidative stress induced by Aβ and α-synuclein. The results of animal experiments also showed that compared with the disease group, DLB rats injected with Liraglutide showed significant improvements of working memory, cognition function and depression by T-maze, object recognition and depression behavior test. In conclusion, our study demonstrated that Liraglutide can attenuate Aβ-induced α-synuclein neurotoxicity in both in in vitro and in vivo models, which may provide a possible treatment strategy for DLB in the future. |
