Evaluation of dopaminergic mechanisms in the DM tau mouse

摘要 精神病性阿尔茨海默病(AD+P)是一种独特的AD变种，具有更快的认知恶化和 加速死亡，缺乏安全有效的治疗。脑脊液生物标志物与神经病理学 研究表明，AD+P是tau磷酸化加速的结果。论小说的发展 治疗AD+P的化合物将通过开发临床前行为模型来促进， 通过神经病理相关性研究，唯一确定tau磷酸化在精神病风险中是可能的。 NIMH研究领域标准(RDoC)倡议提供了一个跨诊断框架 由多巴胺驱动的精神病风险的概念化，并已被纳入一部小说的设计中 AD+P的候选行为模型，其特征是多巴胺能张力增加和 过度磷酸化的tau-DM小鼠。在建议的应用中，将使用DM和其他tau模型 为了研究多巴胺在AD+P的药理诱导范式中的作用，以及为了研究 Tau蛋白磷酸化与精神病相关行为的关系。拟建项目的竣工日期 可能为开发临床前药物途径的进一步研究指明方向 AD+P的治疗进展

ABSTRACT Psychotic Alzheimer’s disease (AD+P) is a distinct AD variant with a more rapid cognitive deterioration and a hastened mortality for which safe and effective treatment is lacking. CSF biomarker and neuropathological studies suggest that AD+P results from an acceleration of tau phosphorylation. The development of novel compounds to treat AD+P would be facilitated by the development of a preclinical behavioral model, made possible by neuropathological correlation studies that uniquely identify tau phosphorylation in psychosis risk. The NIMH Research Domain Criteria (RDoC) initiative provides a framework for the transdiagnostic conceptualization of psychosis risk driven by dopamine, and has been incorporated in the design of a novel candidate behavioral model of AD+P that is characterized by increased dopaminergic tone and hyperphophorylated tau- the DM mouse. In the proposed application the DM and other tau models will be utilized in order to investigate dopamine in a pharmacological induction paradigm of AD+P, and in order to study the relationship between tau phosphorylation and psychosis-relevant behaviors. The completion of the proposed set of experiments may point the way to further research in the development of a preclinical avenue for drug development in the treatment of AD+P.