GLP-1對抗β類澱粉蛋白導致神經毒性之保護作用

阿茲海默症(Alzheimer’s disease)是老年人口最常見的神經性退化性疾病，為失智症中所佔比例最高的一種。已知阿茲海默症患者腦部有兩種重要的病理特徵，分別是類澱粉(amyloid β, Aβ)的斑塊以及神經纖維的纏結，其會造成大量的神經元死亡並使得受影響腦區產生萎縮的現象，最終造成該萎縮腦區所對應的神經功能受損，然而目前臨床上治療阿茲海默症患者的藥物僅能暫時緩解症狀，並無法在根本上改善Aβ的神經毒性，急待開發新型治療策略的藥物。流行病學研究指出，糖尿病患者比起一般正常人多出了65%的機會得到阿茲海默症。近年來研究亦發現阿茲海默症的許多病理特徵，例如腦部細胞死亡和糾結等，似乎確實與胰島素訊息傳遞不正常有關，顯示阿茲海默症很有可能是一種神經內分泌疾病。第二型糖尿病的核心病理特徵為胰島素阻抗，而改善胰島素訊息傳遞的藥物不外乎是增加周邊細胞對於胰島素的敏感性或是增加腸泌素(Glucagon-like peptide-1, GLP-1)的生成，因此被認為具有潛力應用在阿茲海默症的治療方面。我們實驗室先前的研究中已發現，糖尿病用藥DPP-4抑制劑(Dipeptidyl peptidase 4 inhibitor)確實具有對抗Aβ神經毒性的能力，由於DPP-4抑制劑的藥理作用是間接的增加GLP-1之含量，於是在本研究中，我們直接利用GLP-1類似物Liraglutide嘗試作為對抗Aβ的藥物。我們的實驗結果發現GLP-1類似物Liraglutide可抑制pSer307 Insulin receptor substrate 1 (IRS-1)表現，並透過活化AKT來對抗Aβ引起的胰島素阻抗。此外，Liraglutide亦可透透過活化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，並可以刺激nuclear factor erythroid 2-relaated aafactor2 (Nrf-2)、heme oxygenase (HO-1)、Silent information regulator-mammalian ortholog 1 (Sirt1)及superoxide dismutase 1 (SOD-1)的活性，最後減少Aβ誘導的氧化傷害。動物實驗則是透過腦部立體定位手術將GLP-1作為直接注射進腦室，結果顯示注射GLP-1的實驗動物在T迷宮以及物件辨識測驗，其工作記憶及物件辨識記憶功能比起疾病組有明顯的改善，同時海馬迴以及皮質區抗氧化基因Sirt1及SOD-1的表現量有也有明顯增加的現象，但詳細的分子機轉仍需進一步詳細探討。本研究中以細胞實驗及動物實驗證實GLP-1對抗Aβ誘發之神經毒性的保護效果及分子機制，在未來GLP-1或許能夠做為延緩AD患者的病程的治療藥物。

關鍵字

阿茲海默症； β類澱粉蛋白； GLP-1類似物Liraglutide

並列摘要

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elder population, occupying the highest proportion among all types of dementia. As far as we know, there are two important pathological characteristics in AD patients’ brains including amyloid β (Aβ) and neurofibrillary tangles, that cause great numbers of neuronal cell death leading to shrinkage in affected brain regions resulting in deficits in neuronal function. However, the clinical drugs used on AD patients can’t decrease the neurotoxicity of Aβ but only to relief the clinical symptoms. According to epidemiological studies, 65% of type 2 diabetes mellitus (T2DM) patients were more likely to get AD than normal control. Recently, evidence showed several pathological features of AD, such as neuronal cell death and tangles seem to relate to insulin signaling abnormalities. This shows AD may be a type of neuroendocrine disorders. Insulin resistance is a vital mechanism of T2DM, as far as a concern, T2DM drugs can overcome insulin resistance by increasing insulin sensitivity or glucagon-like peptide-1 (GLP-1) production in peripheral cells. According to previous study, we found dipeptidyl peptidase 4 (DPP-4) inhibitor shows ability against neurotoxicity of Aβ, which may indirectly increase the level of GLP-1. To confirm this speculation, we used GLP-1 agonist Liraglutide as a drug to against Aβ in the present study. Our data showed that GLP-1 inhibited phosphorylated insulin receptor substrate 1 (pSer307 IRS-1) expression, and activated AKT in order to fight against insulin resistance induced by Aβ in cellular experiments. Furthermore, GLP-1 activated AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathways, and increased the protein level which related to autophagy. In addition, GLP-1 also stimulated nuclear factor erythroid 2-related factor2 (Nrf-2)、heme oxygenase (HO-1)、silent information regulator-mammalian ortholog 1 (Sirt1) and superoxide dismutase 1 (SOD-1) intracellular expression. Lastly, it could attenuate oxidative damage caused by Aβ. According to the animal model, we demonstrated that injecting GLP-1/ Aβ into ventricle through stereotactic surgery with GLP-1 injection significantly improves working memory and object cognitive recognition ability through T maze test and object recognition test observation in male SD rats comparing to the disease group; accordingly, the mRNA level of SIRT1 and SOD-1 in hippocampus and cortex were also increased. However, it needs further study to clarify the unclear mechanism of GLP-1 against Aβ. In the future, we expect GLP-1 may be use to alleviate Aβ-induced neurotoxicity in Alzheimer’s disease.

並列關鍵字

Alzheimer’s disease ； amyloid β ； GLP-1 agonist Liraglutide

參考文獻

Alzheimer, A., Stelzmann, R. A., Schnitzlein, H. N., & Murtagh, F. R. (1995). An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat, 8(6), 429-431. doi:10.1002/ca.980080612

An, F. M., Chen, S., Xu, Z., Yin, L., Wang, Y., Liu, A. R., . . . Gao, X. D. (2015). Glucagon-like peptide-1 regulates mitochondrial biogenesis and tau phosphorylation against advanced glycation end product-induced neuronal insult: Studies in vivo and in vitro. Neuroscience, 300, 75-84. doi:10.1016/j.neuroscience.2015.05.023

Arnette, D., Gibson, T. B., Lawrence, M. C., January, B., Khoo, S., McGlynn, K., Cobb, M. H. (2003). Regulation of ERK1 and ERK2 by glucose and peptide hormones in pancreatic beta cells. J Biol Chem, 278(35), 32517-32525. doi:10.1074/jbc.M301174200

Athauda, D., & Foltynie, T. (2016). The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action. Drug Discov Today, 21(5), 802-818. doi:10.1016/j.drudis.2016.01.013

Bedse, G., Di Domenico, F., Serviddio, G., & Cassano, T. (2015). Aberrant insulin signaling in Alzheimer's disease: current knowledge. Front Neurosci, 9, 204. doi:10.3389/fnins.2015.00204

國際替代計量

GLP-1對抗β類澱粉蛋白導致神經毒性之保護作用

全文下載

主題瀏覽