阿尔茨海默病与2型糖尿病

火奴鲁鲁-亚洲 胰岛素通 2006 分子机 老年队列 分子机制研究 路受损
PROSPER队 列
ACCORDMIND研究
01 制研究 T2D是AD发病的危险因素 02 2010
2014
糖代谢紊乱
论文 报告会
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来自百度文库
外周→脑内
外周 葡萄糖 AGEs Aβ
炎症因子
AGE受体 （RAGE）
血脑屏障
线粒体 ROS 脑内 炎症因子 Aβ
蛋白质沉积↑ 氧化应激↑ 诱导炎症反应 体(Glucose 调节细胞周期 GLUT) 减少 RAGE结合Aβ→Aβ入脑↑
年份 03
GLUT
血脑屏障（流行病学研究 Blood Brain Barrier, 素抵抗 BBB）破坏 脑血流量（Cerebral Blood Flow, 产物CBF ( Advanced ）↓ 血管病变 d Products, 糖摄取↓ BBB对Aβ清除率↓ 神经元功能障碍
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参考文献
[18]. de la Monte, S.M., Type 3 Diabetes is Sporadic Alzheimer’s disease: Mini-Review. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2014. 24(12): p. 1954-1960. [19]. Simpson, I.A., et al., Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease. Ann Neurol, 1994. 35(5): p. 546-51. [20]. Kalaria, R.N. and S.I. Harik, Abnormalities of the glucose transporter at the blood-brain barrier and in brain in Alzheimer's disease. Prog Clin Biol Res, 1989. 317: p. 415-21. [21]. Winkler, E.A., et al., GLUT1 reductions exacerbate Alzheimer's disease vasculoneuronal dysfunction and degeneration. Nature neuroscience, 2015. 18(4): p. 521-530. [22]. Liu, Y., et al., Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS letters, 2008. 582(2): p. 359-364. [23]. Liu, Y., et al., Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer disease. Journal of neurochemistry, 2009. 111(1): p. 242-249. [24]. Jin, N., et al., CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer’s disease. Nucleic Acids Research, 2013. 41(5): p. 3240-3256. [25]. Correia, S.C., et al., Insulin signaling, glucose metabolism and mitochondria: Major players in Alzheimer's disease and diabetes interrelation. Brain Research, 2012. 1441: p. 64-78. [26]. Srikanth, V., et al., Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease. Neurobiology of Aging, 2011. 32(5): p. 763-777.
恶性循环→认知障碍
神经细胞 胰岛素 受体（IR）
竞 争 胰岛素
胰岛素抵抗
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06
细胞外→细胞内
胰岛素 葡萄糖
细胞膜
IRS PIP2 PI3K Aβ PIP3 MAPK P
GLUT1/3
NFTs
P P P P P
HBP
UDP G
GSK-3β
认知障碍
G Tau蛋白 G P
(
P UDPGlcNac P G
介 绍 相关研究 药物研究 总 结
论文 报告会
总结
糖代谢紊乱 胰岛素 AD AD • 疾病特点 胰岛素通路受损 • 发病机制 血管损伤 胰高血糖素样肽-1 T2D T2D
噻唑烷二酮类
恳请指正！
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参考文献
[1]. World Alzheimer Report 2015: The Global Impact of Dementia | Alzheimer's Disease International. 2016. [2]. Jia, J., et al., The prevalence of dementia in urban and rural areas of China. Alzheimer's & Dementia, 2014. 10(1): p. 1-9. [3]. Guariguata, L., et al., Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Research and Clinical Practice. 103(2): p. 137-149. [4]. Xu, Y., et al., PRevalence and control of diabetes in chinese adults. JAMA, 2013. 310(9): p. 948-959. [5]. GBD, M.A.C.O., Global, regional, and national age-sex specific all-cause and causespecific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet, 2014. 385(9963): p. 117-171. [6]. Ballard, C., et al., Alzheimer's disease. The Lancet. 377(9770): p. 1019-1031. [7]. 刘晓燕与张志珺, Tau蛋白在阿尔茨海默病中的研究进展. 中华脑血管病杂志(电子版), 2011(05): 第411-416页. [8]. Fjell, A.M., et al., What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus. Progress in Neurobiology, 2014. 117: p. 20-40. [9]. Korf, E.S.C., et al., Brain Aging in Very Old Men With Type 2 Diabetes: The HonoluluAsia Aging Study. Diabetes Care, 2006. 29(10): p. 2268 -2274.
G Tau蛋白 G G
G G
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大纲
01 02 03 04
介 绍 相关研究 药 物 总 结
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药物研究
胰岛素
瘦素
二甲双胍？ 治疗糖尿病药物
共同作用靶点药
胰高血糖素样肽-1
噻唑烷二酮类 胰岛淀粉样多肽
二肽基肽酶抑制剂-4 磺酰脲类
非磺酰尿类促泌剂
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大纲
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参考文献
[10]. van Elderen, S.G., et al., Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. Neurology, 2010. 75(11): p. 997-1002. [11]. Profenno, L.A., A.P. Porsteinsson and S.V. Faraone, Meta-Analysis of Alzheimer's Disease Risk with Obesity, Diabetes, and Related Disorders. Biological Psychiatry, 2010. 67(6): p. 505-512. [12]. Gudala, K., et al., Diabetes mellitus and risk of dementia: A meta‐analysis of prospective observational studies. Journal of Diabetes Investigation, 2013. 4(6): p. 640-650. [13]. Sims-Robinson, C., et al., How does diabetes accelerate Alzheimer disease pathology? Nature reviews. Neurology, 2010. 6(10): p. 551-559. [14]. Erus, G., et al., Spatial Patterns of Structural Brain Changes in Type 2 Diabetic Patients and Their Longitudinal Progression With Intensive Control of Blood Glucose. Diabetes Care, 2014. 38(1): p. 97-104. [15]. Moran, C., et al., Brain Atrophy in Type 2 Diabetes: Regional distribution and influence on cognition. Diabetes Care, 2013. 36(12): p. 4036-4042. [16]. Yang, S., et al., Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots. Progress in Neurobiology. [17]. Gray, S.M., R.I. Meijer and E.J. Barrett, Insulin Regulates Brain Function, but How Does It Get There? Diabetes, 2014. 63(12): p. 3992-3997.
阿尔茨海默病与2型糖尿病 的关系及相关药物研究进展
东南大学2011级 焦娇
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大纲
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介 绍 相关研究 药物研究 总 结
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介绍
标准化患病率 4680万 ↑ 6.61%
DM 患病率 • 神经病理学特征： DM 3.82亿 ↑
1. 淀粉样蛋白沉积造成 的老年斑（senile plaque，SP） 2. 过磷酸化tau蛋白形成 的神经纤维缠结 （neurofiberilary tangles, NFT）6,7
2型糖尿病 （Type 2 Diabetes Mellitus, T2D）
11.6%,T2D占90%
阿尔茨海默病 （Alzheimer's Disease, AD）
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大纲
01 02 03 04
介 绍 相关研究 药物研究 总 结
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相关研究
研究名称
血管因素
01 03 02