Brain-Gut Communication in Alzheimer's Disease

 描述(申请人提供)：虽然淀粉样前体蛋白(APP)普遍表达，但由于高水平的神经元表达，与阿尔茨海默病(AD)相关的APP生物学研究的大部分焦点都集中在大脑上。然而，胃肠道的肠道神经系统也表达APP。此外，胃肠道充满了过多的免疫细胞类型，这些细胞不仅广泛地影响肠道的功能，而且还影响包括大脑在内的其他器官系统。认识到这一比较迫使人们考虑AD期间大脑的聚集/沉积与随后的炎症特征是否平行发生在消化道。这意味着有机会对APP相关的生物学或治疗干预进行外围监测，并对AD的病理生理学有了新的理解。更令人兴奋的是，这两个器官系统可能不仅基于免疫细胞的相互作用，而且还基于胃肠道的直接自主神经支配来影响彼此的疾病表型。我们使用转基因阿尔茨海默病小鼠模型的初步数据显示，与大脑的研究结果类似，APP水平增加，肠道中Aü沉积和免疫功能障碍。此外，用治疗性抗体操纵外周免疫系统足以减轻这些小鼠的脑小胶质细胞增多症。最重要的是，我们观察了AD大肠中APP免疫反应性、Aü斑块和含有磷酸化tau的缠结，验证了小鼠模型的相关性。与人类疾病的肠道相比，我们将继续使用最相关的AD小鼠模型来定义大脑和胃肠道疾病之间的时间关系，确定神经元和免疫变化与记忆能力和肠道功能的相关性。我们还将确定APP及其代谢物在调节肠道上皮细胞和免疫细胞表型方面的具体作用。最后，通过改变肠道和大脑的通讯，我们将确定是否有可能通过控制免疫或神经通讯来调节任一器官的疾病进展。

 DESCRIPTION (provided by applicant): Although amyloid precursor protein (APP) is ubiquitously expressed, much of the focus on APP biology with respect to Alzheimer's disease (AD) has focused on the brain due to high levels of neuronal expression. However, the enteric nervous system of the gastrointestinal tract also expresses APP. Moreover, the gastrointestinal tract is filled with a plethora of immune cell types that broadly affect not only the function of te gut but also other organ systems including the brain. Recognition of this comparison forces one to consider whether or not Aß aggregation/deposition with subsequent inflammation characteristic of the brain during AD occurs in parallel in the digestive tract. This suggests an opportunity for peripherally monitoring APP-related biology or therapeutic interventions as well as a novel understanding of the pathophysiology of AD. Even more exciting is the possibility that the two organ systems influence disease phenotype in one another based upon not only immune cell interactions but also the direct autonomic innervation of the gastrointestinal tract. Our preliminary data using a transgenic mouse model of AD demonstrated increased APP levels, Aß deposition and immune dysfunction in the intestines similar to findings from brains. Moreover, manipulation of the peripheral immune system with therapeutic antibodies was sufficient to attenuate brain microgliosis in these mice. Most importantly, we observed APP immunoreactivity, Aß plaques, and phospho-tau containing tangles in AD large intestines validating the relevance of the mouse model. In comparison to human diseased intestines, we will continue using the most relevant mouse models of AD to define the temporal relationship between brain and gastrointestinal disease identifying both neuronal and immune changes in correlation with both memory performance and gut function. We will also determine the specific role of APP and its metabolites in regulating both intestinal epithelial and immune cell phenotypes. Finally, by altering gut-brain communication we will determine whether it is possible to regulate disease progression in either organ by manipulating immune or nervous communication.