2型糖尿病认知障碍发生机制研究进展

摘要/Abstract

摘要： 2型糖尿病是诱发认知障碍的独立危险因素之一，其发病机制除与长期高血糖引起的糖毒性、胆固醇代谢异常密切相关外，还与中枢胰岛素信号转导异常、下丘脑-垂体-肾上腺轴（hypothalamic-pituitary-adrenal axis, HPA）功能亢进有关，而多种生化指标及细胞信号通路的异常不仅增加β淀粉样蛋白引起的神经毒性作用，诱发神经细胞凋亡，而且可加剧脑微血管病变，破坏血脑屏障的正常生理结构及功能，促进2型糖尿病认知障碍的发生发展。本文就2型糖尿病认知障碍进程中的上述关键因子展开讨论，探讨相关防治策略，为开发2型糖尿病认知障碍的治疗药物奠定基础。

关键词: 2型糖尿病, 认知障碍, 糖毒性, 胆固醇代谢, 胰岛素信号, &, beta, 淀粉样蛋白, 血脑屏障

Abstract: Type 2 diabetes mellitus is one of the independent risk factors that can induce cognitive impairment. Except for chronic hyperglycemia-induced glucotoxicity and disorder of cholesterol metabolism, impaired insulin signaling, hyperfunction of HPA axis (hypothalamic-pituitary-adrenal axis) and other factors are also attributed to the pathogenesis of diabetic cognitive dysfunction. Furthermore, many biochemical indicators and abnormal cell signaling pathways not only increase the neurotoxicity of amyloid-β peptide and induce nerve cells apoptosis, but also aggravate cerebral microvessels disease and damage both the structure and function of blood-brain barrier and then promote the occurrence and development of cognitive impairment in type 2 diabetes mellitus. This paper reviewed the key mechanisms in the process of cognitive impairment in type 2 diabetes mellitus and presented the strategies for its prevention and treatment, and subsequently laid the foundation for development of drugs which can effectively treat diabetic cognitive dysfunction.

Key words: type 2 diabetes mellitus, cognitive dysfunction, glucotoxicity, cholesterol metabolism, insulin signaling, amyloid-&, beta, peptide, blood-brain barrier

中图分类号:

陈方, 胡朦, 杜贯涛,刘广军, 洪浩. 2型糖尿病认知障碍发生机制研究进展[J]. 神经药理学报, 2013, 3(3): 27-33.

CHENG Fang, HU Meng, DU Guan-tao, LIU Guang-jun, HONG Hao. Research Advances on Mechanism of Cognitive Impairment in Type 2 Diabetes Mellitus [J]. Acta Neuropharmacologica, 2013, 3(3): 27-33.

参考文献

[1]何斌斌. 糖尿病、糖尿病前期与心血管疾病指南[J]. 糖尿病临床, 2013,7(11):486-505.

[2]Cukierman-Yaffee T. The relationship between dysglycemia and cognitive dysfunction [J]. Curr Opin Investig Drugs, 2009, 10(1):70-74.

[3]Umegaki H, Hayashi T, Nomura H, et al. Cognitive dysfunction: an emerging concept of a new diabetic complication in the elderly [J]. Geriatr Gerontol Int, 2013, 13(1):28-34.

[4] Geert J Biessels. Sweet memories: 20 years of progress in research on cognitive functioning in diabetes [J]. Eur J Pharmacol, 2013, 719(1-3):153-160.

[5] Daniel J Cox, Boris P Kovatchev, Linda A Gonder-Frederick, et al. Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes [J]. Diabetes Care, 2005, 28(1):71-77.

[6] Cristina Carvalho, Paige S Katz, Somhrita Dutta, et al. Increased susceptibility to amyloid-β toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions [J]. J Alzheimers Dis, 2014, 38(1):75-83.

[7]陈刚, 刘淑娟, 傅飞还. 2型糖尿病与认知功能障碍[J].内科理论与实践, 2012, 7(3):160-164.

[8] Sandra J Hamilton, Gerald F Watts. Endothelial dysfunction in diabetes: pathogenesis, significance, and treatment [J]. Rev Diabet Stud, 2013, 10(2-3):133-156.

[9]Singh V P, Bali A, Singh N, et al. Advanced glycation end products and diabetic complications [J]. Korean J Physiol Pharmacol, 2014, 18(1):1-14.

[10]Chen C, Li X H, Tu Y, et al. Aβ-AGE aggravates cognitive deficit in rats via RAG-E pathway [J]. Neuroscience, 2014, 257(17):1-10.

[11]Chen S, An F M, Yin L, et al. Glucagon-like peptide-1 protects hippocampal neurons against advanced glycation end product-induced tau hyperphosphorylation [J]. Neuroscience, 2014, 256:137-146.

[12] George S Bloom. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis [J]. JAMA Neurol, 2014, 71(4):505-508.

[13]Su Shan-yu, Cheng Chin-yi, Tsai Tung-hu, et al. Paeonol attenuates H2O2-induced NF-κB-associat-ed amyloid precursor protein expression [J]. Am J Chin Med, 2010, 38(6):1171-1192.

[14] Linda Chami, Virginie Buggia-Prévot, Eric Duplan, et al. Nuclear factor-κB regulates βAPP and β- and γ-secretases differently at physiological and supraphysiological Aβ concentrations[J]. J Biol Chem, 2012, 287(29):24573-24584.

[15]Xie Jian-ling, Jose D Méndez, Verna Méndez-Valenzuela, et al. Cellular signalling of the receptor for advanced glycation end products (RAGE) [J]. Cell Signal, 2013, 25(11):2185-2197.

[16]Ghribi O, Larsen B, Schrag M, et al. High cholesterol content in neurons increases BACE, β-amyloid, and phosphorylated tau levels in rabbit hippocampus [J]. Exp Neurol, 2006, 200(2):460-467.

[17] Andrew J Beel, Masayoshi Sakakura, Paul J Barrett, et al. Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid-Alzheimer's disease relationships [J]. Biochim Biophys Acta, 2010, 1801(8):975-982.

[18] Makoto Michikawa. Cholesterol paradox: is high total or low HDL cholesterol level a risk for Alzheimer's disease [J]. J Neurosci Res, 2003, 72(2):141-146.

[19] Andrew B Wolf, Richard J Caselli, Eric M Reiman, et al. APOE and neuroenergetics: an emerging p-aradigm in Alzheimer's disease [J]. Neurobiol Aging, 2013, 34(4):1007-1017.

[20]Vance J E, Karten B, Hayashi H. Lipid dynamics in neurons [J]. Biochem Soc Trans, 2006, 34(Pt 3):399-403.

[21]刘文, 张宁. 载脂蛋白E与糖尿病[J].东南大学学报:医学版, 2014, 33(2):231-234.

[22] Michael Malek-Ahmadi, Thomas Beach, Aleksandra Obradov, et al. Increased Alzheimer's disease neuropathology is associated with type 2 diabetes and ApoE ε. 4 carrier status [J]. Curr Alzheimer Res, 2013, 10(6):654-659.

[23] Jochen Walter. γ-Secretase, apolipoprotein E and cellular cholesterol metabolism [J]. Curr Alzheimer Res, 2012, 9(2):189-199.

[24] David M Holtzman, Joachim Herz, Bu Guo-jun. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease [J]. Cold Spring Harb Perspect Med, 2012, 2(3):a006312.

[25] Andrew B Wolf, Jon Valla, Bu Guo-jun, et al. Apolipoprotein E as a β-amyloid-independent factor in Alzheimer's disease [J]. Alzheimers Res Ther, 2013, 5(5):38.

[26] Adam R Cole, Arlene Astell, Charlotte Green, et al. Molecular connexions between dementia and diabetes [J]. Neurosci Biobehav Rev, 2007, 31(7):1046-1063.

[27] Bordier L, Doucet J, Boudet J, et al. Update on cognitive decline and dementia in elderly patients with diabetes [J]. Diabetes Metab, 2014, pii: S1262-3636.

[28]Fernanda G De Felice. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications [J]. J Clin Invest, 2013, 123(2):531–539.

[29]Xian Yan-fang, Mao Qing-qiu, Justin CY Wu, et al. Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau p-rotein hyperphosphorylation [J]. J Alzheimers Dis, 2014, 39(2):331-346.

[30] Suzanne M de la Monte. Contributions of brain insulin resistance and deficiency in a-myloid-related neurodegeneration in Alzheimer's disease [J]. Drugs, 2012, 72(1):49-66.

[31] Chen Zhi-chun, Zhong Chun-jiu. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies [J]. Prog Neurobiol, 2013, 108:21–43.

[32] Li Bing, Yu Da-wei, Xu Zhi-ying, et al. Activated protein C inhibits amyloid-β production via promoting expression of ADAM-10 [J]. Brain Res, 2014, 30:1545:35-44.

[33]Yang Y, Song W, et al. Molecular links between Alzheimer's disease and diabetes mellitus [J]. Neuroscience, 2013, 250:140-150.

[34] Shingo Ito, Sumio Ohtsuki, Sho Murata, et al. Involvement of insulin-degrading enzyme in insulin and atrial natriuretic peptide-sensitive internalization of amyloid-β peptide in mouse brain capillary endothelial cells [J]. J Alzheimers Dis, 2014, 38(1):185-200.

[35] Pamela Salcedo-Tello, Karina Hernández-Ortega, Clorinda Arias, et al. Susceptibility to GSK3β-induc-ed tau phosphorylation differs between the young and aged hippocampus after Wnt sig-naling inhibition [J]. J Alzheimers Dis, 2014, 39(4):775-785.

[36] Shashi Kant Tiwari, Swati Agarwal, Brashket Seth, et al. Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer's disease model via can-onical Wnt/β-catenin pathway [J]. ACS Nano, 2014, 8(1):76-103.

[37] Aniko Varadi, Takashi Tsuboi, Linda I Johnson-Cadwell, et al. Kinesin I and cytoplasmic dynein orchestrate glucose-stimulated insulin-containing vesicle movements in clonal MIN6 beta-cells [J].Biochem Biophys Res Commun, 2003, 311(2):272-282.

[38] Michelle Carey, Sylvia Kehlenbrink, Meredith Hawkins, et al. Evidence for central regulation of glucose metabolism [J]. J Biol Chem, 2013, 288(49):34981-34988.

[39] Jamaica R Rettberg, Yao Jia, Roberta D Brinton. Estrogen: a master regulator of bioenergetic systems in the brain and body [J]. Front Neuroendocrinol, 2014, 35(1):8-30.

[40] Hannah Bruehl, Melanie Rueger, Isabel Dziobek, et al. Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes [J]. J Clin Endocrinol Metab, 2007, 92(7):2439-2445.

[41] Manuel Gil-Lozano, Marina Romaní-Pérez, Veronica Outeiriño-Iglesias, et al. Effects of prolonged e-xendin-4 administration on hypothalamic-pituitary-adrenal axis activity and water balance [J]. Am J Physiol Endocrinol Metab, 2013, 304(10):E1105-E1117.

[42]Amin S N, Younan S M, Youssef M F, et al. A histological and functional study on hippocampal formation of normal and diabetic rats [J]. F1000Res, 2013, 2:151.

[43]Soares E, Prediger R D, Nunes S, et al. Spatial memory impairments in a prediabetic rat model [J]. Neuroscience, 2013, 250:565-577.

[44] Claire Allen, Kirtiman Srivastava, Ulvi Bayraktutan. Small GTPase RhoA and its effector rho kinase mediate oxygen glucose deprivation-evoked in vitro cerebral barrier dysfunction [J]. Stroke, 2010, 41(9):2056-2063.

[45] Joe M Chehade, Michael J Haas, Arshag D Mooradian. Diabetes-related changes in rat cerebral occludin and zonula occludens-1 (ZO-1) expression [J]. Neurochem Res, 2002, 27(3):249-252.

[46]VanGilder R L, Kelly K A, Chua M D, et al. Administration of sesamol improved blood-brain barrier function in streptozotocin-induced diabetic rats [J]. Exp Brain Res, 2009, 197(1):23-34.

[47]Kook Sun-young, Hyun Seok Hong, Moon M, et al. Disruption of blood-brain barrier in Alzheimer disease pathogenesis [J]. Tissue Barriers, 2014, 1(2):e23993.

[48]Ning Rui-zhuo, Michael Chopp, Alex Zacharek, et al. Neamine induces neuroprotection after acute ischemic stroke in type one diabetic rats [J]. Neuroscience, 2014, 257:76-85.

[49]Hong Hao, Liu Li-ping, Liao Jian-ming, et al. Downregulation of LRP1 at the blood-brain barrier in streptozotocin-induced diabetic mice [J]. Neuropharmacology, 2013, 56(6-7):1054-1059.

[50]Kook S Y, Hong H S, Moon M, et al. Aβ1-42-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca²+-calcineurin signaling [J]. J Neurosci, 2012, 32(26):8845-8854.

[51] Shingo Ito, Sumio Ohtsuki, Tetsuya Terasaki. Functional characterization of the brain-to-blood effluxclearance of human amyloid-beta peptide (1-40) across the rat blood-brain barrier [J]. Neurosci Res, 2006, 56(3):246-252.

[52] Ewan C McNay, AK Recknagel. Brain insulin signaling: a key component of cogni-tive processes and a potential basis for cognitive impairment in type 2 diabetes [J]. Neurobiol Learn Mem, 2011, 96(3):432-442.

[53]Chen Yao-min, Zhou Kun, Wang Rui-shan, et al. Antidiabetic drug metformin (Glucophager) increases biogenesis of Alzheimer's amyloid peptides via up-regulating bace1 transcription [J]. Proc Natl Acad Sci USA, 2009, 106(10):3907－3912.

[54]Wang Li, Yu Chun-Jiang, Liu Wei, et al. Rosiglitazone protects neuroblastoma cells against advanced glycation end products-induced injury [J]. Acta Pharmacol Sin, 2011, 32(8):991-998.

[55]Li Ya-zhou, Kara B Duffy, Mary Ann Ottinger, et al. GLP-1 receptor stimulation reduces amyloid-pep-tide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease [J]. J Alzheimers Dis, 2010, 19(4):1205-1219.

[56] Noppamas Pipatpiboon, Hiranya Pintana, Wasana Pratchayasakul, et al. DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption [J]. Eur J Neurosci, 2013, 37(5):839-849.

[57] Zina Kroner. The relationship between Alzheimer's disease and diabetes: Type 3 diabetes [J]. Altern Med Rev, 2009, 14(4):373-379.

[58]Zhang Yi, Zhou Ben, Zhang Fang, et al. Amyloid-β induces hepatic insulin resistance by activating JAK2/STAT3/SOCS-1 signaling pathway [J]. Diabetes, 2012, 61(6):1434-1443.

[59]Zhang Yi, Zhou Ben, Deng Bo, et al. Amyloid-β induces hepatic insulin resistance in vivo via JAK2[J]. Diabetes, 2013, 62(4):1159-1166.