阿尔茨海默病合并2型糖尿病模型小鼠海马血管损伤与认知改变

陈小平; 邢彦伟; 闫朝霞; 常红叶; 陈贝贝; 范文娟

doi:10.16098/j.issn.0529-1356.2021.06.004

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解剖学报 ›› 2021, Vol. 52 ›› Issue (6) : 863-869. DOI: 10.16098/j.issn.0529-1356.2021.06.004

神经生物学

阿尔茨海默病合并2型糖尿病模型小鼠海马血管损伤与认知改变

陈小平¹邢彦伟² 闫朝霞¹常红叶¹ 陈贝贝¹ 范文娟^3*

作者信息 +

Hippocampal vascular injury and cognitive impairment in a mixed mouse models of Alzheimer’s disease and type 2 diabetes mellitus

CHEN Xiao-ping¹ XING Yan-wei² YAN Zhao-xia¹ CHANG Hong-ye¹ CHEN Bei-bei¹ FAN Wen-juan^3*

Author information +

文章历史 +

摘要

目的探讨2型糖尿病（T2DM）对阿尔茨海默病（AD）脑血管发育的影响，及其对AD病理发生的影响机制。方法 40只6月龄APP/PS1转基因小鼠及同窝野生型小鼠采用高糖高脂饲料喂养6个月后，即各组小鼠12月龄时，连续4 d腹腔注射 1% 链脲佐菌素溶液，建立AD合并T2DM模型小鼠及单纯T2DM模型小鼠。设立4个组别：正常对照组、AD组、T2DM组、AD合并T2DM组，每组小鼠各10只。通过小鼠跳台实验检测小鼠学习记忆能力，墨汁灌注观察小鼠海马区血管形态，油红O染色、免疫荧光实验检测小鼠海马区各病理指标变化。结果与正常对照组相比，AD合并T2DM模型小鼠学习与记忆能力明显下降(P<0.05)，海马区血管变细、密度明显减低(P<0.05)，脂质沉积增多并出现小血管渗漏，且其海马区β-淀粉样前体蛋白裂解酶1（BACE-1）、核因子（NF)-κB与基质金属蛋白酶（MMP)-9表达增多(P<0.05)。结论 T2DM对小鼠学习记忆功能起负作用，通过促进AD病理变化加速AD模型小鼠脑血管病变，MMP-9的异常表达也可能是引起AD血管病变的原因之一。

Abstract

Objective To study the effect of type 2 diabetes mellitus (T2DM) on the cerebral blood vessels in Alzheimer’s disease (AD), and to explore its mechanism of influence on the pathogenesis of Alzheimer’s disease. Methods To generate a mouse model with AD complicated with long-term T2DM, forty 6-month-old APP/PS1 transgenic mice were fed with high-sugar and high-fat diet for 6 months, that was, when mice at 12 months of age, they were intraperitoneally injected with 1% streptozotocin solution for 4 consecutive days. Then, mice were randomly divided into 4 groups: the normal control group, AD model group, T2DM model group and AD complicated with T2DM model group, 10 mice were used in each group. The learning and memory ability of the mice were tested by the mouse step-down assay, and the vascular morphology of the mice’s hippocampal CA1 area was observed by ink perfusion. Then oil red O staining and immunofluorescent staining were applied to test the pathological indices of the hippocampal area in the model. Results Compared with the control group, AD combined with T2DM mice showed decreasing significantly abilities in the learning and memory (P<0.05), and the blood vessels in the hippocampus became thinner and the vascular density decreased. Moreover, T2DM promoted lipid deposits and vascular leak in the hippocampus of the model. Additionally, the expression of β-site amyloid precursor protein cleaving enzyme-1(BACE-1), nuclear factor(NF)-κB and matrix metalloproteinase(MMP)-9 were increased compared with the controls in the hippocampal CA1 region. Conclusion T2DM plays a negative regulatory role on learning and memory functions of mice, accelerates the onset of AD and result in cerebrovascular lesions. In addition, the abnormal expression of MMP-9 may also be one of the causes of AD vascular lesions.

导出引用

陈小平邢彦伟闫朝霞常红叶陈贝贝范文娟. 阿尔茨海默病合并2型糖尿病模型小鼠海马血管损伤与认知改变[J]. 解剖学报. 2021, 52(6): 863-869 https://doi.org/10.16098/j.issn.0529-1356.2021.06.004

CHEN Xiao-ping XING Yan-wei YAN Zhao-xia CHANG Hong-ye CHEN Bei-bei FAN Wen-juan. Hippocampal vascular injury and cognitive impairment in a mixed mouse models of Alzheimer’s disease and type 2 diabetes mellitus[J]. Acta Anatomica Sinica. 2021, 52(6): 863-869 https://doi.org/10.16098/j.issn.0529-1356.2021.06.004

中图分类号： Q189

参考文献

［1］ Sengoku R. Aging and Alzheimer’s disease pathology［J］. Neuropathology, 2020,40(1):22-29.

［2］ Hanseeuw BJ, Scott MR, Sikkes S, et al. Evolution of anosognosia in alzheimer’s disease and its relationship to amyloid［J］. Ann Neurol, 2020,87(2):267-280.

［3］ Schubert D. Glucose metabolism and Alzheimer’s disease［J］. Ageing Res Rev, 2005,4(2):240-257.

［4］ Cho S, Lee H, Seo J. Impact of genetic risk factors for Alzheimer’s disease on brain glucose metabolism［J］. Mol Neurobiol, 2021,58(6):2608-2626.

［5］ Chornenkyy Y, Wang WX, Wei A, et al. Alzheimer’s disease and type 2 diabetes mellitus are distinct diseases with potential overlapping metabolic dysfunction upstream of observed cognitive decline［J］. Brain Pathol, 2019,29(1):3-17.

［6］ Pilipenko V, Narbute K, Beitnere U, et al. Very low doses of muscimol and baclofen ameliorate cognitive deficits and regulate protein expression in the brain of a rat model of streptozocin-induced Alzheimer’s disease［J］. Eur J Pharmacol, 2018,818:381-399.

［7］Wang Q, Fan WJ, Sun YZh, et al. Kinesin1-mediated neuronal axoplasmic transport disorder in cerebral cortex of amyloid precursor protein/presenilin-1 transgenic mice［J］. Acta Anatomica Sinica, 2018,49(2):158-165. (in Chinese)

王倩, 范文娟, 孙仪征, 等. 淀粉样蛋白前体/早老素1转基因小鼠大脑皮质内kinesin1介导的神经元轴浆运输障碍［J］. 解剖学报, 2018,49(2):158-165.

［8］ Steinman J, Sun HS, Feng ZP. Microvascular alterations in Alzheimer’s Disease［J］. Front Cell Neurosci, 2020,14:618986.

［9］ Barbagallo M, Dominguez LJ. Type 2 diabetes mellitus and Alzheimer’s disease［J］. World J Diabetes, 2014,5(6):889-893.

［10］ Pereira JD, Fraga VG, Santos ALM, et al. Alzheimer’s disease and type 2 diabetes mellitus: A systematic review of proteomic studies［J］. J Neurochem, 2020, 156(6): 753-776.

［11］ Tumminia A, Vinciguerra F, Parisi M, et al. Type 2 diabetes mellitus and Alzheimer’s disease: role of insulin signalling and therapeutic implications［J］. Int J Mol Sci, 2018,19(11): 3306.

［12］ van der Kant R, Goldstein L, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease［J］. Nat Rev Neurosci, 2020,21(1):21-35.

［13］ Kent SA, Spires-Jones TL, Durrant CS. The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics［J］. Acta Neuropathol, 2020,140(4):417-447.

［14］ Malkki H. Alzheimer disease: Insulin resistance could be linked to risk of AD via reduced glucose uptake［J］. Nat Rev Neurol, 2015,11(9):485.

［15］ Sweeney MD, Montagne A, Sagare AP, et al. Vascular dysfunction-the disregarded partner of Alzheimer’s disease［J］. Alzheimers Dement, 2019,15(1):158-167.

［16］ Reilly AM, Tsai AP, Lin PB, et al. Metabolic defects caused by high-fat diet modify disease risk through inflammatory and amyloidogenic pathways in a mouse model of alzheimer’s disease［J］. Nutrients, 2020,12(10):2977.

［17］ Bracko O, Vinarcsik LK, Cruz Hernández JC, et al. High fat diet worsens Alzheimer’s disease-related behavioral abnormalities and neuropathology in APP/PS1 mice, but not by synergistically decreasing cerebral blood flow［J］. Sci Rep, 2020,10(1):9884.

［18］ Nizari S, Carare RO, Hawkes CA. Increased Aβ pathology in aged Tg2576 mice born to mothers fed a high fat diet［J］. Sci Rep, 2016,6:21981.

［19］ Cai ZhY, Zhao B. Molecular Biology of Alzheimer’s Disease［M］. Beijing: Science Press, 2016: 159-190.

蔡志友, 赵斌. 阿尔茨海默病分子生物学［M］. 北京: 科学出版社, 2016: 159-190.

［20］ Schultz N, Br ?nnstr?m K, Byman E, et al. Amyloid-beta 1-40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro［J］. Aging Cell, 2018,17(3):e12728.

［21］ Maesako M, Uemura K, Kuzuya A, et al. Presenilin regulates insulin signaling via a gamma-secretase-independent mechanism［J］. J Biol Chem, 2011,286(28):25309-25316.

［22］ Beroun A, Mitra S, Michaluk P, et al. MMPs in learning and memory and neuropsychiatric disorders［J］. Cell Mol Life Sci, 2019,76(16):3207-3228.

［23］ Rivera S, García-González L, Khrestchatisky M, et al. Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other neurodegenerative disorders［J］. Cell Mol Life Sci, 2019,76(16):3167-3191.

［24］ Bruno MA, Mufson EJ, Wuu J, et al. Increased matrix metalloproteinase 9 activity in mild cognitive impairment［J］. J Neuropathol Exp Neurol, 2009,68(12):1309-1318.