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，并用于开发新的药物以及改进现有的药物，例如那些在阿尔茨海默病进展早期增加胆碱能神经传递的药物。在PPG目前的五年里，子项目2率先使用液相色谱联用串联质谱法对脑组织进行蛋白质组学检查，以研究AD疾病进展过程中的蛋白质组学。这些努力导致在阿尔茨海默病（AD）中发现Ul小核核糖核蛋白（Ul snRNP）成分的病理积累和RNA加工的整体破坏。我们将应用这些创新的蛋白质组学方法以及完善的生化和免疫组织化学方法来：1)确定在AD进展过程中，由Meynert基底核内长皮质胆碱能投射神经元广泛支配的记忆默认网络皮层区域内Ul snRNP的病理积累；翻译后修饰的tau蛋白，以及在AD进展过程中定义胆碱能基底前脑神经元亚野功能障碍的新蛋白，以及3)在AD进展过程中检测与胆碱能基底前脑神经元内Ul snRNP病理相关的RNA加工变化。这些拟议的研究将提高我们对Ul snRNP在AD发生和进展中的作用的理解，并可能发现新的疾病介质。这些进展对于促进我们对阿尔茨海默病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.