Mechanisms contributing to co-morbid psychosis in Alzheimer's disease

项目摘要/摘要： 精神病症状(幻觉和妄想)是非常普遍的阿尔茨海默病。不幸的是， 用于治疗精神病的抗精神病药物在老年人中是禁忌的，因为食物和药物 美国食品药品监督管理局(FDA)对所有第一代和第二代抗精神病药物发布了黑盒警告 这表明这些药物增加了老年痴呆症患者的死亡风险。我们已经证明了 海马体在多巴胺系统功能的调节中起着中心作用，而这种异常 海马多巴胺神经元活动的调节可能与精神分裂症的精神障碍有关。考虑到 海马区是阿尔茨海默病的关键病理部位，我们推测海马区可能是AD的汇聚部位 我们将使用啮齿动物模型来研究这一假说。具体来说， 我们将检查多巴胺神经元活动的基础活动和传入调节，以及行为相关。 两种不同的阿尔茨海默病啮齿动物模型中精神病的发生率(目标1)。然后我们将检查AD病理的后果 关于vHipp中间神经元功能以及干细胞来源的中间神经元移植(AIM 2)或 药理调节海马区功能(Aim 3)可逆转异常神经元活动和 AD模型中的行为。这项建议因此确定了一个潜在的新的治疗靶点，并向 开发更有效的治疗阿尔茨海默病和共病精神病的方法。

Project Summary/Abstract: Psychotic symptoms (hallucinations and delusions) are highly prevalent Alzheimer's disease. Unfortunately, the antipsychotic medications used to treat psychosis are contraindicated in the elderly where the Food and Drug Administration (FDA) issued a black-box warning for all first- and second-generation antipsychotic medications indicating that these drugs increase the risk of death in elderly dementia patients. We have demonstrated that the hippocampus plays a central role in the regulation of dopamine system function and that aberrant hippocampal regulation of dopamine neuron activity likely contributes to psychosis in schizophrenia. Given that the hippocampus is a key site of pathology in AD, we posit that the hippocampus may be a site of convergence contributing to comorbid psychosis in AD, and we will use rodent models to study this hypothesis. Specifically, we will examine basal activity and afferent regulation of dopamine neuron activity as well as behavioral correlates of psychosis in two distinct rodent models of AD (Aim 1). We will then examine the consequence of AD pathology on vHipp interneuron function and whether transplantation of stem cell derived interneurons (Aim 2) or pharmacological modulation of hippocampal function (Aim 3) can reverse aberrant neuronal activity and behavior in AD models. This proposal with therefore identify a potential novel therapeutic target and inform the development of more effective treatment approaches for AD and comorbid psychosis.