高胆固醇对认知功能障碍及Aβ代谢的影响

发布时间：2018-04-10 21:25

  本文选题：高胆固醇 + 认知功能障碍　； 参考：《第三军医大学》2017年硕士论文

【摘要】：研究背景认知功能障碍包括轻度认知损害(MCI)和痴呆,在老年人群发生率较高,预计到2050年全球认知功能障碍患者将远超1.5亿。认知功能障碍可显著影响患者本人生活质量,大量认知功能障碍患者给其家庭同时给社会都带来了破坏性的影响。目前关于认知功能障碍尚无有效的治疗方法,对其进行一级预防尤为重要。探索认知功能障碍发生的危险因素及发生的机制能够为其防治提供重要的理论依据。国内外大量研究表明高血压、糖尿病等血管危险因素可以增加认知功能障碍的风险。然而,关于高胆固醇与认知功能障碍之间关系的前瞻性研究较少,相关机制尚不清楚,并且未得出一致的结论。有研究认为高胆固醇血症可增加阿尔茨海默病(AD)和血管性痴呆(VD)的认知功能损害程度,但也有学者认为血浆胆固醇水平降低可以加剧认知功能的减退。因此,高胆固醇血症是否增加认知功能障碍的风险尚有较大争议。AD是认知功能障碍中最常见的疾病。在动物模型中已经证明高胆固醇可以增加脑内β淀粉样蛋白(Aβ)的含量,促进脑内Ab的积聚,与AD老年斑的形成密切相关,但高胆固醇导致脑内Ab积聚的机制仍不清楚。Science上发表的一篇研究认为Aβ在脑内清除转运的平衡机制可能也参与了脑内Ab的积聚过程。高胆固醇是否会通过影响Aβ跨血脑屏障的转运进而导致脑内Ab积聚尚不清楚。阐明高胆固醇对Aβ跨血脑屏障转运机制的影响,对于进一步探索高胆固醇导致认知功能障碍发生的机制具有重要意义。本研究将从临床和基础两个方面进行研究。第一部分为临床研究,探讨高胆固醇血症与认知功能障碍的关系及对Aβ代谢的影响;第二部分为实验研究,通过脑微血管内皮细胞Aβ转运受体的表达,探讨高胆固醇对Aβ代谢的影响。第一部分高胆固醇对认知功能障碍及Aβ代谢影响的临床研究目的:在60岁以上的老年人群中,探讨高胆固醇血症与认知功能障碍发生的关系,以及认知功能障碍发生中高胆固醇对血清Aβ水平的影响,为认知功能障碍的防治提供临床依据。方法:收集2015年3月至2015年12月于我科住院无认知功能障碍的患者,进行1年的随访。入组时收集血脂指标及他汀类药物使用情况,通过简易精神状态量表(MMSE)评估其认知功能。根据末次随访时MMSE评分分为认知功能正常组及认知功能障碍组。随机抽取高胆固醇血症和无高胆固醇血症患者各20例,末次随访时收集血液标本通过ELISA试剂盒检测血清Aβ1-40及Aβ1-42水平。分析高胆固醇血症及他汀类药物治疗与认知功能障碍的关系,并分析高胆固醇血症对血清Aβ水平的影响。结果:1.基线共纳入388例患者,平均年龄为71.27±8.042岁,其中男性202例(52.1%),女性186例(47.9%)。384例(99.0%)患者完成1年的随访,其中高胆固醇血症患者177例(46.1%),认知功能障碍患者62例(16.1%)。2.认知功能障碍组与认知功能正常组相比,患者年龄较大;男性比例较高;高血压、糖尿病及高胆固醇血症患者比例较高;脑白质病变(WML)分值、血清低密度脂蛋白胆固醇(LDL-C)及糖化血红蛋白(HbA1c)水平较高;使用他汀类药物的患者比例较低,以上差异均具有统计学意义(P0.05)。3.高胆固醇血症患者血清Aβ1-40水平及血清Aβ1-42水平均显著低于无高胆固醇血症患者(P(27)0.05)。4.认知功能各个方面中,高胆固醇血症患者基线视空间与执行功能、注意力及计算力、语言及抽象能力等认知功能分值均显著低于无高胆固醇血症患者(P0.05),但高胆固醇血症组仅视空间及执行功能1年内下降分值显著高于无高胆固醇血症组(P0.05)。5.调整了年龄、性别、高血压、糖尿病、Hb A1c及WML等因素的影响后,二分类logistic回归显示,高胆固醇血症(OR:3.013,95%CI:1.628-5.164,P(27)0.05)及血清LDL-C水平(OR:1.676,95%CI:1.200-2.222,P(27)0.05)与认知功能障碍的发生密切相关,而他汀药物使用(OR:0.799,95%CI:0.361-0.974,P(27)0.05)与认知功能障碍呈负相关。结论:1.高胆固醇血症尤其血清LDL-C水平增高可以增加认知功能障碍发生的风险。2.高胆固醇血症组血清Aβ水平低于无高胆固醇血症组。3.高胆固醇血症与认知功能障碍中执行功能减退密切相关。4.他汀类药物的使用可以降低认知功能障碍发生的风险。第二部分高胆固醇对Aβ代谢影响的实验研究目的:探索高胆固醇对小鼠脑微血管内皮细胞Aβ转运受体LRP-1和RAGE表达的影响,为研究高胆固醇导致认知功能障碍发生的机制提供实验依据。方法:分离培养年轻小鼠(C57BL/6,6-8周龄)及老年鼠(C57BL/6,12月龄)脑微血管内皮细胞,分别进行正常培养(正常小鼠组、正常老年鼠组)和高胆固醇处理培养(高胆固醇小鼠组、高胆固醇老年鼠组),通过QPCR法和Western Blot法分别检测各组LRP-1及RAGE mRNA和蛋白的表达。结果:1.正常小鼠组、正常老年鼠组、高胆固醇小鼠组及高胆固醇老年鼠组LRP-1mRNA(F=64.317,P(27)0.001)及蛋白(F=522.205,P(27)0.001)表达呈递减趋势。各组间两两比较,正常老年鼠组、高胆固醇小鼠组及高胆固醇老年鼠组LRP-1 mRNA(P(27)0.05)及蛋白(P(27)0.001)表达量均明显低于正常小鼠组,高胆固醇小鼠组及高胆固醇老年鼠组LRP-1 m RNA及蛋白表达量与正常老年鼠相比,均显著下降(P(27)0.05),高胆固醇老年鼠组LRP-1 m RNA及蛋白表达量低于高胆固醇小鼠组,差异有统计学意义(P(27)0.05)。2.正常小鼠组、正常老年鼠组、高胆固醇小鼠组及高胆固醇老年鼠组RAGE mRNA(F=146.999,P(27)0.001)及蛋白(F=879.362,P(27)0.001)表达呈递增趋势。各组间两两比较,正常老年鼠组、高胆固醇小鼠组及高胆固醇老年鼠组RAGE m RNA(P(27)0.05)及蛋白(P(27)0.001)表达量均明显高于正常小鼠组,高胆固醇小鼠组及高胆固醇老年鼠组RAGE m RNA(P(27)0.001)及蛋白(P(27)0.05)表达量与正常老年鼠相比,均显著增高,高胆固醇老年鼠组RAGE m RNA(P(27)0.001))及蛋白(P(27)0.05)表达量高于高胆固醇小鼠组,差异有统计学意义。结论:在高胆固醇状态下,小鼠脑微血管内皮细胞LRP-1表达量下降,RAGE表达量增高,提示高胆固醇通过影响Aβ转运蛋白,进而影响Aβ的转运清除,增加认知功能损害的风险。
[Abstract]:Backgroundcognitive dysfunction including mild cognitive impairment (MCI) and dementia in the elderly population, high incidence rate, is expected to 2050 global cognitive dysfunction will be far more than 150 million. Cognitive dysfunction can significantly affect the quality of life of the patient, a large number of patients with cognitive impairment to their families and society to have devastating effects on the treatment. There is no effective method for cognitive dysfunction, for the primary prevention of the particularly important. To explore the risk factors of cognitive dysfunction and the mechanism can provide important theoretical basis for its prevention and treatment. A large number of domestic and foreign research shows that hypertension, vascular risk factors such as diabetes can increase the risk of cognitive impairment. However, prospective studies on the relationship between high cholesterol and cognitive dysfunction is less, related mechanism is not clear, and did not come to the same Conclusion. Studies have suggested that high cholesterol can increase Alzheimer's disease (AD) and vascular dementia (VD) and the degree of cognitive impairment, but also some scholars believe that the reduction of plasma cholesterol levels decline may enhance cognitive function. Therefore, whether hypercholesterolemia increases the risk of cognitive dysfunction is still controversial.AD is the most common disease. Cognitive dysfunction in animal models has shown that high cholesterol can increase brain amyloid beta (A beta) content, promote the accumulation of Ab in the brain, and is closely related to the formation of AD plaque, but the mechanisms leading to high cholesterol in the brain of Ab accumulation is still not clear in a study published in the.Science. Think of A beta in the brain to clear the balance mechanism of transport may also be involved in the accumulation of Ab in the brain. Whether high cholesterol will be influenced by the beta A cross the blood-brain barrier and brain Ab accumulated in transport It is unclear. To clarify the effects of high cholesterol on A beta across the blood brain barrier transporter mechanism, to further explore the mechanism of cognitive dysfunction associated with high cholesterol has important significance. This research will study from two aspects. The first part is the basis of clinical and clinical research, explore the hypercholesterolemia and cognitive dysfunction and effect of A beta metabolism; the second part is the experimental research, through the expression of brain microvascular endothelial cells A beta transport receptor, to investigate the effects of high cholesterol on A beta metabolism. Objective to evaluate the clinical results of the first part of high cholesterol on cognitive dysfunction and metabolic effects of A beta: Elderly people over the age of 60, to explore the relationship between high cholesterol and cognitive dysfunction, and cognitive dysfunction in high cholesterol effect on serum A, for the prevention and treatment of cognitive dysfunction in clinical According to. Methods: from March 2015 to December 2015 in our hospital without cognitive impairment patients, followed up for 1 years. When the group collected blood fat index and statin use by mini mental state examination (MMSE) to assess the cognitive function. According to the MMSE scores were divided into normal cognitive function group and cognitive dysfunction group randomly. Hypercholesterolemia and hypercholesterolemia were 20 cases each, at the end of the follow-up blood samples collected by serum A detection kit 1-40 beta ELISA and A beta 1-42. Analysis of the relationship between high cholesterol and statins therapy and cognitive dysfunction, and analyze the effect of hypercholesterolemia the serum A. Results: 1. baseline included 388 patients with an average age of 71.27 + 8.042 years, including 202 cases of male female 186 cases (52.1%), (47.9%).384 cases (99%) patients completed 1 years with Visit, including 177 cases of patients with hypercholesterolemia (46.1%), 62 cases of patients with cognitive impairment (16.1%) compared to the.2. cognitive dysfunction group and cognitive function in the normal group, the patients were older; the higher proportion of males; hypertension, diabetes and hypercholesterolemia, a higher proportion of patients; cerebral white matter lesions (WML) score, serum low density lipoprotein protein cholesterol (LDL-C) and glycosylated hemoglobin (HbA1c) level is higher; the use of statins in patients with a lower proportion, the above differences were statistically significant (P0.05 1-40) level and serum A beta.3. hypercholesterolemia serum A beta 1-42 levels were significantly lower than non patients with hypercholesterolemia (P (27) 0.05) the cognitive function of.4. in patients with hypercholesterolemia, baseline visual spatial and executive function, attention and computing power, language ability and abstract cognitive function scores were significantly lower than non patients with hypercholesterolemia (P0.05 ), but high cholesterol group only visual spatial and executive function within 1 years of decline were significantly higher than those without hypercholesterolemia group (P0.05.5.) adjusted for age, sex, hypertension, diabetes mellitus, and the effect of Hb A1c WML and other factors, two classification logistic regression showed that hypercholesterolemia (OR:3.013,95%CI:1.628-5.164, P (27) 0.05) and the serum level of LDL-C (OR:1.676,95%CI:1.200-2.222, P (27) 0.05) closely associated with cognitive dysfunction, and statin use (OR:0.799,95%CI:0.361-0.974, P (27) 0.05) was negatively correlated with cognitive impairment. Conclusions: 1. hypercholesterolemia especially elevated serum LDL-C level can increase the incidence of cognitive dysfunction the risk of.2. hypercholesterolemia serum beta A level is lower than the executive function without hypercholesterolemia group.3. hypercholesterolemia and cognitive dysfunction in hypothyroidism is closely related to.4. use of statins You can reduce the risk of cognitive dysfunction. Objective to study on effect of second high cholesterol on A beta metabolism: To explore the effects of high cholesterol on mice brain microvascular endothelial cells A beta transport receptor LRP-1 and RAGE expression, and provide experimental basis for the study of mechanism of cognitive dysfunction associated with high cholesterol. Methods: cultured young mice (C57BL/6,6-8 weeks old) and aged rats (C57BL/6,12 months) of brain microvascular endothelial cells were cultured in normal (normal mice group, normal rats group) and high cholesterol treatment (Gao Dan sterol mice group, high cholesterol group of aged rats), the expression levels of LRP-1 and RAGE mRNA and protein were detected by QPCR method the Western and Blot method. Results: 1. normal mice group, normal rats group, high cholesterol group and high cholesterol mouse aged rats group LRP-1mRNA (F=64.317, P (27) and protein (F=522.20 0.001) 5,P(27)0.001)琛ㄨ揪鍛堥，

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