背景唐氏综合征(DS)与阿尔茨海默病(AD)密切相关,归因于APP过度表达。DS表现出与早发性AD(EOAD)和晚发性AD(LOAD)相似的淀粉样蛋白-β(Aβ)和Tau病理学。本研究旨在评估DS的Aβ斑块蛋白质组,EOAD和负载。方法采用无偏定位蛋白质组学,我们分析了四个队列(n=20/组)中来自死后石蜡包埋组织的淀粉样蛋白斑块和邻近的无斑块组织(“非斑块”):DS(59.8±4.99y/o),EOAD(63±4.07y/o),负荷(82.1±6.37y/o)和对照(66.4±13.04)。我们使用基因本体论(GO)富集和蛋白质相互作用网络评估功能关联。结果我们鉴定了差异丰富的Aβ斑块蛋白与非斑块(FDR<5%,DS的倍数变化>1.5)(n=132),EOAD(n=192)和LOAD(n=128);所有组间共有43种斑块相关蛋白。在DS和EOAD(R2=0.77)中观察到斑块相关蛋白之间存在正相关(p<0.0001),DS和LOAD(R2=0.73),和EOAD与荷载(R2=0.67)。顶级生物过程(BP)GO项(p<0.0001)包括DS的溶酶体转运,EOAD的免疫系统调节,和LOAD的溶酶体组织。蛋白质网络在所有涉及APP代谢的队列中显示出斑块丰富的特征,免疫反应,和溶酶体功能。在DS中,EOAD和LOAD非斑块vs.控制组织,我们鉴定了263、269和301种差异丰富的蛋白质,包括所有队列中65种改变的非斑块蛋白。与EOAD(R2=0.59)和LOAD(R2=0.33)相比,DS中差异丰富的非斑块蛋白显示出显着(p<0.0001),但与EOAD(R2=0.79)和LOAD(R2=0.33)的正相关较弱。所有组的前BPGO术语是染色质重塑(DSp=0.0013,EOADp=5.79x10-9,和负载p=1.69x10-10)。DS的其他GO项包括细胞外基质(p=0.0068),而EOAD和LOAD与蛋白质-DNA复合物和基因表达调控相关(p<0.0001)。结论我们发现DS患者的Aβ斑块蛋白质组之间有很强的相似性,EOAD和LOAD,以及斑块蛋白质组与溶酶体和免疫相关途径之间的紧密关联。Further,非斑块蛋白质组强调了与染色质结构和细胞外基质(ECM)相关的改变途径,后者特别与DS相关。我们鉴定了新的Aβ斑块蛋白,它可以作为生物标志物或治疗靶标。
UNASSIGNED: Down syndrome (DS) is strongly associated with Alzheimer\'s disease (AD), attributable to APP overexpression. DS exhibits Amyloid-β (Aβ) and Tau pathology similar to early-onset AD (EOAD) and late-onset AD (LOAD). The study aimed to evaluate the Aβ plaque proteome of DS, EOAD and LOAD.
UNASSIGNED: Using unbiased localized proteomics, we analyzed amyloid plaques and adjacent plaque-devoid tissue (\'non-plaque\') from post-mortem paraffin-embedded tissues in four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o) and controls (66.4 ± 13.04). We assessed functional associations using Gene Ontology (GO) enrichment and protein interaction networks.
UNASSIGNED: We identified differentially abundant Aβ plaque proteins vs. non-plaques (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192) and in LOAD (n = 128); there were 43 plaque-associated proteins shared between all groups. Positive correlations (p < 0.0001) were observed between plaque-associated proteins in DS and EOAD (R2 = 0.77), DS and LOAD (R2 = 0.73), and EOAD vs. LOAD (R2 = 0.67). Top Biological process (BP) GO terms (p < 0.0001) included lysosomal transport for DS, immune system regulation for EOAD, and lysosome organization for LOAD. Protein networks revealed a plaque enriched signature across all cohorts involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, including 65 altered non-plaque proteins across all cohorts. Differentially abundant non-plaque proteins in DS showed a significant (p < 0.0001) but weaker positive correlation with EOAD (R2 = 0.59) and LOAD (R2 = 0.33) compared to the stronger correlation between EOAD and LOAD (R2 = 0.79). The top BP GO term for all groups was chromatin remodeling (DS p = 0.0013, EOAD p = 5.79×10- 9, and LOAD p = 1.69×10- 10). Additional GO terms for DS included extracellular matrix (p = 0.0068), while EOAD and LOAD were associated with protein-DNA complexes and gene expression regulation (p < 0.0001).
UNASSIGNED: We found strong similarities among the Aβ plaque proteomes in individuals with DS, EOAD and LOAD, and a robust association between the plaque proteomes and lysosomal and immune-related pathways. Further, non-plaque proteomes highlighted altered pathways related to chromatin structure and extracellular matrix (ECM), the latter particularly associated with DS. We identified novel Aβ plaque proteins, which may serve as biomarkers or therapeutic targets.