Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer's Disease
Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer's Disease
复制标题
DOI：
10.3389/fnmol.2018.00454
复制
发表时间：
2018-12-18
影响因子：
4.8
通讯作者：
Seyfried, Nicholas T.
中科院分区：
文献类型：
--
作者：
Dai, Jingting;Johnson, Erik C. B.;Seyfried, Nicholas T.
载脂蛋白E（APOE）基因的多态性等位基因是晚发性阿尔茨海默病（AD）风险的主要遗传决定因素。与携带更常见的E3等位基因的个体相比，携带APOE E4等位基因的个体患AD的风险增加，而携带E2等位基因的个体患AD的风险降低。Apoe亚型如何影响AD的风险仍不清楚。为了帮助填补这一知识空白，我们进行了一个比较公正的基于质谱的蛋白质组学分析，从病理定义的AD或不同APOE基因型的对照病例的死后脑皮质组织。对照组（n = 10）为常见E3等位基因纯合型，而AD组（n = 24）E2/3、E3/3和E4/4基因型平均分布。我们使用差异蛋白表达和共表达分析方法来评估大脑蛋白质组的变化与APOE基因型的关系。我们观察到与E3/3和E4/4 AD脑相比，E2/3脑中淀粉样蛋白β水平相似，但神经胶质tau水平降低。加权共表达网络分析显示共表达蛋白33个模块，其中12个模块在AD中的APOE基因型之间存在显著差异。APOE基因型显著不同的模块与突触传递和炎症以及其他生物学过程相关。脑细胞类型变化的去卷积和分析显示，E2等位基因抑制星形胶质细胞、小胶质细胞、少突胶质细胞和内皮细胞的稳态和疾病相关细胞类型变化。E2等位基因对脑细胞类型变化的特异性作用在130个大脑的单独队列中得到验证。我们对AD脑的系统水平蛋白质组学分析揭示了与APOE等位基因变异相关的脑蛋白质组和脑细胞类型的改变，并建议进一步研究推动ApoE相关AD风险的上游机制。
Polymorphic alleles in the apolipoprotein E (APOE) gene are the main genetic determinants of late-onset Alzheimer's disease (AD) risk. Individuals carrying the APOE E4 allele are at increased risk to develop AD compared to those carrying the more common E3 allele, whereas those carrying the E2 allele are at decreased risk for developing AD. How ApoE isoforms influence risk for AD remains unclear. To help fill this gap in knowledge, we performed a comparative unbiased mass spectrometry-based proteomic analysis of post-mortem brain cortical tissues from pathologically-defined AD or control cases of different APOE genotypes. Control cases (n = 10) were homozygous for the common E3 allele, whereas AD cases (n = 24) were equally distributed among E2/3, E3/3, and E4/4 genotypes. We used differential protein expression and co-expression analytical approaches to assess how changes in the brain proteome are related to APOE genotype. We observed similar levels of amyloid-beta, but reduced levels of neurofibrillary tau, in E2/3 brains compared to E3/3 and E4/4 AD brains. Weighted co-expression network analysis revealed 33 modules of co-expressed proteins, 12 of which were significantly different by APOE genotype in AD. The modules that were significantly different by APOE genotype were associated with synaptic transmission and inflammation, among other biological processes. Deconvolution and analysis of brain cell type changes revealed that the E2 allele suppressed homeostatic and disease-associated cell type changes in astrocytes, microglia, oligodendroglia, and endothelia. The E2 allele-specific effect on brain cell type changes was validated in a separate cohort of 130 brains. Our systems-level proteomic analyses of AD brain reveal alterations in the brain proteome and brain cell types associated with allelic variants in APOE, and suggest further areas for investigation into the upstream mechanisms that drive ApoE-associated risk for AD.