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

阿尔茨海默病共病精神病的机制

• 批准号: 10012453
• 负责人: Daniel Lodge
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012453
• 关键词: Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Antipsychotic Agents; Autopsy; Behavior; Behavioral; Belief; Cell Transplantation; Delusions; Dementia; Development; Disease; Dopamine; Elderly; Electrophysiology (science); Exons; Functional disorder; Generations; Glutamates; Hallucinations; Hippocampus (Brain); Human; Interneuron function; Interneurons; Knock-in; Locomotion; Memory; Midbrain structure; Military Personnel; Modeling; Mutation; Neurons; Parvalbumins; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Play; Population; Post-Traumatic Stress Disorders; Prevalence; Psychoses; Rattus; Regulation; Reporting; Rodent Model; Role; Schizophrenia; Services; Signal Transduction; Site; Somatostatin; Stem cell transplant; Structure; Swedish mutation; Symptoms; Therapeutic; Toxic effect; Transplantation; Traumatic Brain Injury; United States Food and Drug Administration; Ventral Tegmental Area; Veterans; associated symptom; care costs; cholinergic; comorbidity; disorder risk; dopamine system; dopaminergic neuron; effective therapy; extracellular; in vivo; military veteran; mortality risk; neurotransmission; new therapeutic target; novel; novel therapeutic intervention; positive allosteric modulator; prepulse inhibition; presenilin-1; preservation; psychotic symptoms; receptor; response; spatial memory

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.

项目概要/摘要： 精神病症状（幻觉和妄想）是非常普遍的阿尔茨海默病。可惜 用于治疗精神病的抗精神病药物在老年人中是禁忌的， FDA对所有第一代和第二代抗精神病药物发出了黑盒警告 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 海马体在多巴胺系统功能的调节中发挥着核心作用，而异常的 海马调节多巴胺神经元活性可能有助于精神分裂症的精神病。鉴于 海马是AD的一个重要病理部位，我们认为海马可能是AD的一个会聚部位， 我们将使用啮齿动物模型来研究这一假设。具体地说， 我们将研究多巴胺神经元活动的基础活动和传入调节以及行为相关性 精神病在两个不同的啮齿类动物模型的AD（目的1）。然后我们将研究AD病理学的后果 对vHipp中间神经元功能的影响，以及移植干细胞衍生的中间神经元（目的2）或 海马功能的药理学调节（目的3）可以逆转异常的神经元活性， AD模型中的行为。因此，该提议确定了一个潜在的新治疗靶点，并告知 为AD和共病精神病开发更有效的治疗方法。