Abstract：
Selective neuronal vulnerability (SNV) of specific neuroanatomical regions such as frontal cortex (FC) and hippocampus (HC) is characteristic of age-associated neurodegenerative diseases (NDDs), although its pathogenetic basis remains unresolved. We hypothesized that physiological differences in mitochondrial function in neuroanatomical regions could contribute to SNV. To investigate this, we evaluated mitochondrial function in human brains (age range:1-90 y) in FC, striatum (ST), HC, cerebellum (CB) and medulla oblongata (MD), using enzyme assays and quantitative proteomics. Striking differences were noted in resistant regions- MD and CB compared to the vulnerable regions- FC, HC and ST. At younger age (25 ± 5 y), higher activity of electron transport chain enzymes and upregulation of metabolic and antioxidant proteins were noted in MD compared to FC and HC, that was sustained with increasing age (≥65 y). In contrast, the expression of synaptic proteins was higher in FC, HC and ST (vs. MD). In line with this, quantitative phospho-proteomics revealed activation of upstream regulators (ERS, PPARα) of mitochondrial metabolism and inhibition of synaptic pathways in MD. Microtubule Associated Protein Tau (MAPT) showed overexpression in FC, HC and ST both in young and older age (vs. MD). MAPT hyperphosphorylation and the activation of its kinases were noted in FC and HC with age. Our study demonstrates that regional heterogeneity in mitochondrial and other cellular functions contribute to SNV and protect regions such as MD, while rendering FC and HC vulnerable to NDDs. The findings also support the \"last in, first out\" hypothesis of ageing, wherein regions such as FC, that are the most recent to develop phylogenetically and ontogenetically, are the first to be affected in ageing and NDDs.
摘要：
特定神经解剖区域如额叶皮质(FC)和海马(HC)的选择性神经元易损性(SNV)是年龄相关性神经退行性疾病(NDD)的特征。尽管其致病基础仍未解决。我们假设神经解剖区域线粒体功能的生理差异可能导致SNV。为了调查这一点，我们评估了FC中人脑的线粒体功能（年龄范围：1-90岁），纹状体(ST),HC,小脑（CB）和延髓（MD），使用酶测定和定量蛋白质组学。与脆弱地区-FC相比，抗性地区-MD和CB出现了惊人的差异，HC和ST。在较年轻的年龄（25±5岁），与FC和HC相比，MD的电子传递链酶活性更高，代谢和抗氧化蛋白上调。随着年龄的增长（≥65岁）而持续。相比之下,突触蛋白在FC中表达较高，HC和ST（vs.MD）。与此相符,定量磷酸蛋白质组学揭示了上游调节因子的激活(ERS，PPARα）在MD中的线粒体代谢和突触途径的抑制。微管相关蛋白Tau（MAPT）在FC中显示过表达，年轻和老年的HC和ST(vs.MD）。随着年龄的增长，在FC和HC中注意到MAPT过度磷酸化及其激酶的激活。我们的研究表明，线粒体和其他细胞功能的区域异质性有助于SNV和保护区域，如MD，同时使FC和HC容易受到NDD的影响。调查结果也支持“最后在，首先“衰老的假设”，其中FC等区域，是最新的系统发育和个体发育，是第一个受到衰老和NDD影响的人。
