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

阿尔茨海默病共病精神病的机制

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

Affect Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

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项目摘要

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.

项目摘要/摘要：精神病症状（幻觉和妄想）是高度普遍的阿尔茨海默氏病。不幸的是，用于治疗精神病的抗精神病药是在食品和药物的老年人中禁忌的管理（FDA）发出了所有第一代抗精神病药物的黑盒警告表明这些药物增加了老年痴呆症患者死亡的风险。我们已经证明了海马在多巴胺系统功能的调节中起着核心作用，并且异常多巴胺神经元活性的海马调节可能导致精神分裂症的精神病。鉴于海马是AD中病理的关键部位，我们认为海马可能是收敛的位置促进AD合并症的精神病，我们将使用啮齿动物模型来研究这一假设。具体来说，我们将检查多巴胺神经元活性的基础活性和传入调节以及行为相关性在两个不同的AD啮齿动物模型中精神病（AIM 1）。然后，我们将检查AD病理学的后果关于VHIPP中间神经元功能以及干细胞衍生的中间神经元的移植（AIM 2）或海马功能的药理调节（AIM 3）可以逆转异常的神经元活性和广告模型中的行为。因此，该提案确定了潜在的新型治疗靶点并告知开发用于AD和合并症的更有效的治疗方法。