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Alzheimer`s & Dementia: 前沿! 理论完善: 低水平补体C3是阿尔兹海默症(AD)的一个高风险因子

LTNeurosci 逻辑神经科学 2019-06-30
Comparison of a normal aged brain (left) and the brain of a person with Alzheimer's (right). Characteristics that separate the two are pointed out.

随着全球范围内人均寿命的延长,阿尔兹海默症(Alzheimer`s disease,AD)严重危害着人们的晚期生活;目前仍没有有效的治疗途径。所以,鉴定出具有因果关系通路的生物标志物,对于理解AD疾病机制、提供靶向治疗具有重要意义【1-2】

全基因组关联性研究表明,补体受体基因(complement receptor 1 gene, CR1突变与AD的发生和进展有关,也就是说CR1在AD发病机理存有补体相关的通路【3-4】CR1与载脂蛋白E基因APOEε4的相互作用可以引起认知能力下降和痴呆【3, 5】。动物模型和人类解剖学的研究也揭示出,补体与小神经胶质细胞在β淀粉样蛋白斑块聚集的神经病理学中伴有有益和有害的双重角色【6-7】

Complement component 3,简称补体C3,一种免疫系统中的蛋白质,在补体系统中起着核心作用,且有益于先天性免疫;位于人19号染色体上的C3基因可编码补体C3【8-9】。换言之,C3是补充系统激活的核心成分,其表达水平也反映了激活的潜力【10】

尽管,有研究暗示出高水平C3或许与肥胖、胰岛素抗性、糖尿病、血脂异常及心血管代谢等疾病的病发有关【10】,但是,在AD小鼠模型中,已经确切证实了补体C3的缺乏/不足会导致β淀粉样蛋白斑块的聚集、神经退化等【7】

2018年9月19日,来自(丹麦)哥本哈根大学医院、卫生与医学科学院的联合研究团队,将他们的一项前沿性研究成果以An updated Alzheimer hypothesis: Complement C3 and risk of Alzheimer`s disease — A cohort study of 95,442 individuals 题在线发表在Alzheimer`s & Dementia(IF = 12.740)上。

研究表明:血浆中低水平补体C3是AD的一个高风险因子,且在APOEɛ44基因携带个体中,C3诱发AD的风险会被放大;孟德尔随机化实验进而佐证了这种因果关系【11】

在本研究中,研究者们将揭示低血浆水平的C3与AD高风险之间的关系,进而以孟德尔随机化实验对这一关系进行验证(Mendelian randomization: an epidemiological approach that aims to limit the influence of confounding and reverse causation by the use of genetic variants in human populations)【12】

为了达到研究目的,研究者们对CGPS(Copenhagen General Population Study)中的95442个体进行了研究,包括:(1)补体C3的血浆基线测量;(2)rs1065489,rs429608和rs448260的基因型分析,进而确定C3表达水平;(3). 对CGPS中的特定个体进行近13年(中位数: 8年)跟踪观察AD的发展情况(table 1)(4)最后,对CCHS(Copenhagen City Heart Study)中的8367个体也进行了遗传学分析。

Fig. 3  Risk of Alzheimer’s disease as a function of one standard deviation increase and of tertiles of plasma complement C3. Hazard ratios were multifactorially adjusted for age (time scale), sex, body mass index, smoking, hypertension, diabetes, lipid-lowering therapy, alcohol consumption, physical inactivity, education, postmenopausal status, and hormonal replacement therapy (left panel), and further for plasma CRP (right panel); 1 SD increase in C3 5 0.21 g/L. Abbreviations: C3, complement C3; 95% CI, 95% confidence interval; CRP, Creactive protein; SD, standard deviation.

整体结果表明:(1). 在所有个体中,且在较低水平C3的一个标准偏差下,多因素调整后的AD风险比hazard ratio)为1.1,95% 置信区间1.04-1.19;另外,在APOEε44基因携带中,AD风险比是1.66,置信区间为1.33-2.07 (Fig. 1)

(2)在孟德尔随机化实验中,所有个体的AD风险比为1.66,置信区间1.05-2.63;而在APOEε44基因携带中,AD风险比则为1.99,置信区间为0.52-7.65 (Fig. 2)

Fig. 4  Risk of Alzheimer’s disease for observational and for causal, genetically determined plasma complement C3 for all APOE genotypes and for APOE ε44 only. Observational hazard ratios for CGPS as well as stage 2 models used for genetic estimates for CGPS and CCHS were age (timescale) and sex adjusted Cox regression models. Follow-up time for individuals in the CCHS was truncated to median follow-up for the CGPS (8.2years). For the genetic estimates for CGPS and CCHS,we used a weighted gene score, which was the sum of weights, with the per genotype weights being the β-coefficients for the three variants obtained from a linear regression. R2 is 1%, and the F-statistics is 1392 for the weighted gene score; 1 SD increase in C3 5=0.21 g/L. Abbreviations: 95% CI, 95% confidence interval; APOE, apolipoprotein E gene; C3, complement C3; CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; SD, standard deviation.

总的来说,低基线水平的补体C3会诱发AD,是AD的一个高风险因子,同时在APOEε44基因敏感个体中,C3诱发AD风险将会大大升高;同时,孟德尔随机化实验进而佐证了低水平C3与AD高风险间的因果关系,即低水平C3易诱发AD。最终,研究者们完善了低水平C3与AD高风险的关系理论。

补充阅读

【1】Nature:重磅!清除衰老的神经胶质细胞,可以阻止tau蛋白沉积和认知能力下降(长文解析)

【2】Neuron:前沿!Tau蛋白会破坏阿尔茨海默氏病(AD)的核质转运(新机制)

【3】Science:前沿!成人神经细胞再生与BDNF的共操作可作为阿尔兹海默症(AD)的一种强有力治疗途径

【4】JEM:前沿!TLR5诱骗受体可作为治愈阿尔兹海默症(AD)的一种新颖且安全的免疫调节剂

【5】Brain: HSPA2被确定为晚发型阿尔兹海默症的一个关键驱动因子

参考文献

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【8】M H de Bruijn and G H Fe. Human complement component C3: cDNA coding sequence and derived primary structure. Proc. Natl. Acad. Sci. USA 1985; 82:708-712,

【9】Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol  2007; 171:715–27.

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【11】Katrine Laura Rasmussen,  Børge Grønne Nordestgaard , Ruth Frikke-Schmid, Sune Fallgaard Nielsen. An updated Alzheimer hypothesis: Complement C3 and risk of Alzheimer’s disease—A cohort study of 95,442 individuals. Alzheimer’s & Dementia 2018; DOI: https://doi.org/10.1016/j.jalz.2018.07.223.

【12】Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey SG. Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology. Stat Med  2008; 27:1133–63.


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