Jaeger Philipp A, Lucin Kurt M, Britschgi Markus, Vardarajan Badri, Huang Ruo-Pan, Kirby Elizabeth D, Abbey Rachelle, Boeve Bradley F, Boxer Adam L, Farrer Lindsay A, Finch NiCole, Graff-Radford Neill R, Head Elizabeth, Hofree Matan, Huang Ruochun, Johns Hudson, Karydas Anna, Knopman David S, Loboda Andrey, Masliah Eliezer, Narasimhan Ramya, Petersen Ronald C, Podtelezhnikov Alexei, Pradhan Suraj, Rademakers Rosa, Sun Chung-Huan, Younkin Steven G, Miller Bruce L, Ideker Trey, Wyss-Coray Tony
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Institute of Chemistry and Biochemistry, Free University Berlin, Berlin, Germany.
Mol Neurodegener. 2016 Apr 26;11:31. doi: 10.1186/s13024-016-0095-2.
Biological pathways that significantly contribute to sporadic Alzheimer's disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.
To access this information we probed relative levels of close to 600 secreted signaling proteins from patients' blood samples using antibody microarrays and mapped disease-specific molecular networks. Using these networks as seeds we then employed independent genome and transcriptome data sets to corroborate potential pathogenic pathways.
We identified Growth-Differentiation Factor (GDF) signaling as a novel Alzheimer's disease-relevant pathway supported by in vivo and in vitro follow-up experiments, demonstrating the existence of a highly informative link between cellular pathology and changes in circulatory signaling proteins.
对散发性阿尔茨海默病有显著影响的生物学途径在很大程度上尚不清楚，且无法直接观察到。认知症状在分子疾病发作数十年后才出现，这使得分析更加复杂。因此，分子研究通常局限于脑组织的晚期尸检研究。然而，疾病过程预计会触发众多细胞信号通路并调节局部和全身环境，分泌信号分子的由此产生的变化携带着关于原本无法获取的病理过程的信息。
为了获取这些信息，我们使用抗体微阵列检测了患者血液样本中近600种分泌信号蛋白的相对水平，并绘制了疾病特异性分子网络。然后，以这些网络为种子，我们利用独立的基因组和转录组数据集来证实潜在的致病途径。
我们将生长分化因子（GDF）信号传导确定为一条与阿尔茨海默病相关的新途径，体内和体外后续实验均支持这一结论，证明了细胞病理学与循环信号蛋白变化之间存在高度信息丰富的联系。
