Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer's disease progression.
Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer's disease progression.
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嗅球神经蛋白质组学揭示了在阿尔茨海默氏病进展过程中生存途径的时间顺序扰动和破坏防止蛋白复合物。
DOI：
10.1038/s41598-017-09481-x
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发表时间：
2017-08-22
影响因子：
4.6
通讯作者：
Santamaría E
中科院分区：
文献类型：
--
作者：
Lachén-Montes M;González-Morales A;Zelaya MV;Pérez-Valderrama E;Ausín K;Ferrer I;Fernández-Irigoyen J;Santamaría E
嗅觉功能障碍是阿尔茨海默病（AD）的最早特征之一。虽然在嗅球（OB）中发现了神经病理学异常，但对其动态生物学知之甚少。在这里，OB-蛋白质组分析表明，在AD的发展阶段依赖性突触蛋白质稳态损害。除了tau和淀粉样前体蛋白（APP）相互作用组的进行性调节外，网络驱动蛋白质组学揭示了AD受试者OB中上游和下游p38 MAPK通路的早期破坏以及随后的磷酸肌醇依赖性蛋白激酶1（PDK 1）/蛋白激酶C（PKC）信号传导轴的损伤。此外，线粒体失衡证明了在中期和晚期AD阶段的抑制素-2（Phb 2）水平的耗竭和磷酸化的Phb 1亚型的特定减少。有趣的是，嗅觉Phb亚基也在不同类型的痴呆症中失调。Phb 2在混合型痴呆中表现出特异性上调，而Phb 1亚型在额颞叶变性（FTLD）中下调。然而，没有观察到差异Phb亚基的嗅觉表达进行性核上性麻痹（PSP）。总之，我们的数据部分反映了AD嗅觉功能障碍的生化理解中缺失的环节，揭示了Phb复合物作为嗅觉水平神经变性的差异驱动因素。
Olfactory dysfunction is among the earliest features of Alzheimer’s disease (AD). Although neuropathological abnormalities have been detected in the olfactory bulb (OB), little is known about its dynamic biology. Here, OB- proteome analysis showed a stage-dependent synaptic proteostasis impairment during AD evolution. In addition to progressive modulation of tau and amyloid precursor protein (APP) interactomes, network-driven proteomics revealed an early disruption of upstream and downstream p38 MAPK pathway and a subsequent impairment of Phosphoinositide-dependent protein kinase 1 (PDK1)/Protein kinase C (PKC) signaling axis in the OB from AD subjects. Moreover, a mitochondrial imbalance was evidenced by a depletion of Prohibitin-2 (Phb2) levels and a specific decrease in the phosphorylated isoforms of Phb1 in intermediate and advanced AD stages. Interestingly, olfactory Phb subunits were also deregulated across different types of dementia. Phb2 showed a specific up-regulation in mixed dementia, while Phb1 isoforms were down-regulated in frontotemporal lobar degeneration (FTLD). However, no differences were observed in the olfactory expression of Phb subunits in progressive supranuclear palsy (PSP). To sum up, our data reflect, in part, the missing links in the biochemical understanding of olfactory dysfunction in AD, unveiling Phb complex as a differential driver of neurodegeneration at olfactory level.
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