Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach
Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach
复制标题
神经退行性疾病认知功能减退的突触标志物：蛋白质组学研究
DOI：
10.1093/brain/awx352
复制
发表时间：
2018-02-01
期刊：
影响因子：
14.5
通讯作者：
Aarsland, Dag
中科院分区：
文献类型：
--
作者：
Bereczki, Erika;Branca, Rui M.;Aarsland, Dag
在神经退行性疾病的发病机制中发生的认知变化与突触丢失直接相关。我们使用深入的蛋白质组学来比较32个死后人脑的前额叶皮层，这些大脑是前瞻性随访的阿尔茨海默病患者、帕金森病痴呆患者、路易体痴呆患者和无痴呆的老年人。我们总共鉴定了10325种蛋白质，其中851种是突触蛋白。25种突触蛋白的水平在不同的痴呆组中显著改变。使用ELISA或蛋白质印迹在由92个脑样品组成的较大群组上进一步验证SNAP 47、GAP 43、SYBU（突触结合蛋白）、LRFN2、SV2C、SYT2（突触结合蛋白2）、GRIA3和GRIA4的显著损失。死亡前认知功能障碍和认知功能下降率与SNAP 47、SYBU、LRFN2、SV2C和GRIA3蛋白的丢失显著相关。除了以高灵敏度和特异性将帕金森病痴呆、路易体痴呆和阿尔茨海默病与对照区分开之外，突触蛋白还可靠地将帕金森病痴呆与阿尔茨海默病患者区分开。我们的研究结果表明，这些特定的突触蛋白在神经退行性疾病中具有重要的预测和鉴别分子指纹，并可能成为早期疾病干预的潜在靶点。
Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. We used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospectively followed patients with Alzheimer's disease, Parkinson's disease with dementia, dementia with Lewy bodies and older adults without dementia. In total, we identified 10 325 proteins, 851 of which were synaptic proteins. Levels of 25 synaptic proteins were significantly altered in the various dementia groups. Significant loss of SNAP47, GAP43, SYBU (syntabulin), LRFN2, SV2C, SYT2 (synaptotagmin 2), GRIA3 and GRIA4 were further validated on a larger cohort comprised of 92 brain samples using ELISA or western blot. Cognitive impairment before death and rate of cognitive decline significantly correlated with loss of SNAP47, SYBU, LRFN2, SV2C and GRIA3 proteins. Besides differentiating Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson's disease dementia from Alzheimer's disease patients. Our results suggest that these particular synaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and could be a potential target for early disease intervention.