Determinants of Neurodegeneration in the Evolution of MCI and AD

了解阿尔茨海默病(AD)的发病需要开发新的研究方法，这些方法可以应用于临床前疾病和产生新的药物，以及改进现有的药物，如那些在AD进展早期增强胆碱能神经传递的药物。在PPG目前的五年中，子项目2开创了使用高效液相色谱结合串联质谱仪对脑组织进行蛋白质组学检查的方法，以研究AD疾病进展过程中的蛋白质组。这些努力导致在阿尔茨海默病(AD)中发现了Ul小核核糖核蛋白(Ul SnRNP)成分的病理性积聚和RNA加工的全球中断。我们将应用这些创新的蛋白质组学方法以及成熟的生化和免疫组织化学方法来1)确定Ul SnRNP在皮质区域的病理性积聚，该区域构成记忆默认网络，在AD进展期间接受来自Meynert基底核亚场内的长皮质胆碱能投射神经元的广泛胆碱能神经支配；2)确定Ul SnRNP成分的变化、tau的翻译后修饰，以及定义AD进展过程中胆碱能基础前脑神经元亚场功能障碍的新蛋白；以及3)检测AD进展期间与Ul SnRNP病理相关的RNA处理的变化。这些拟议的研究将提高我们对Ul snRNP在AD发生和发展中的作用的理解，并可能识别新的疾病介质。这些进展对于促进我们对AD的理解和开发更有效的治疗方法至关重要。

Understanding the onset of Alzheimer's disease (AD) requires the development of new research methods, which can be applied to preclinical disease and for the generation of new as well as the improvement of currently available drugs such as those which augment cholinergic neurotransmission early in the progression of AD. During the current five years of the PPG, subproject 2 has pioneered methods for using liquid chromatography coupled with tandem mass spectrometry for proteomic examination of brain tissue to study the proteome of AD during disease progression. These efforts led to the discovery of pathological accumulations of components of the Ul small nuclear ribonucleoprotein (Ul snRNP) and global disruption of RNA processing in Alzheimer's disease (AD). We will apply these innovative proteomics approaches along with well-established biochemical and immuohistochemical methods to 1) define pathological accumulations of Ul snRNP within the cortical regions which compose the memory default network which receive extensive cholinergic innervation from the long cortical cholinergic projection neurons located within the subfields of the nucleus basalis of Meynert during progression of AD, 2) Identify changes in Ul snRNP components, posttranslational modifications of tau, and novel proteins that define cholinergic basal forebrain neuron subfield dysfunction that follows a caudal to rostral progression the during progression of AD, and 3) examine changes In RNA processing linked to Ul snRNP pathology within the cholinergic basal forebrain neurons during the progression of AD. The proposed studies will improve our understanding ofthe role of Ul snRNP in the development and progression of AD, and likely to identify novel mediators of disease. Such advances are critical to advancing our understanding of AD and the development of more effective therapeutics.