GHSR1a and Hippocampal Pathology in Alzheimer's Disease

阿尔茨海默病中的 GHSR1a 和海马病理学

• 批准号: 10163763
• 负责人: Heng Du
• 金额: $ 45.27万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163763
• 关键词: Abeta synthesis; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Disease Models; Apoptosis; Apoptotic; Binding; Binding Sites; Cells; Cellular Stress; Characteristics; Cognitive deficits; Complex; Data; Defect; Dementia; Dendritic Spines; Development; Disease; Dopamine D1 Receptor; Evaluation; Exhibits; Functional disorder; GHS-R1a; Hippocampus (Brain); Hypothalamic structure; Impaired cognition; Impairment; In Vitro; Injury; Knockout Mice; Lead; Learning; Ligands; Light; Link; Mediating; Mediator of activation protein; Membrane; Memory; Molecular; Molecular Conformation; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Predisposition; Principal Investigator; Protein Analysis; Protein Isoforms; Regulation; Reporting; Role; Signal Pathway; Slice; Somatotropin; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Transmembrane Domain; abeta accumulation; aging population; behavior test; density; experimental study; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; human tissue; improved; in vivo; increased appetite; memory consolidation; mouse model; neuron loss; neuronal survival; novel; novel strategies; patch clamp; preservation; programs; synaptic function; therapeutic target; treatment strategy

Characterized by progressive cognitive decline, Alzheimer's disease (AD) is the most common type of dementia primarily attacking the aging population. Hippocampal synaptic injury and neurodegeneration are defining pathological features of the cognitive deficits in Alzheimer's disease (AD). In order to better understand the pathogenesis of the disease, and to improve AD treatment options, we need to elucidate the molecular mechanisms that cause cellular stress in the hippocampus. The growth hormone secretagogue receptor (GHSR), also known as ghrelin receptor, is highly expressed in neurons of the hypothalamus and hippocampus. In addition to its roles in stimulating appetite and growth hormone release, recent studies have revealed an important contribution of GHSR1a, the functional isoform of GHSR, in the regulation of hippocampal synaptic plasticity and memory consolidation. GHSR1a heteromerizes with the dopamine receptor D1 (DRD1), thus regulating DRD1-mediated modulation of synaptic plasticity. Moreover, recent studies have shown GHSR1a- dependent apoptosis of hippocampal neurons, indicating a critical role for GHSR1a in hippocampal neuronal survival. GHSR-null mice exhibit hippocampal pathology and cognitive impairments that resemble AD-like symptoms. In preliminary studies we found substantially reduced GHSR1a/DRD1 heteromerization in hippocampal tissue from human AD cases, as well as in an AD mouse model (5xFAD mice), even though the expression levels of membrane-bound GHSR1a and DRD1 remained relatively preserved. In addition, our preliminary studies revealed an unexpected physical interaction between GHSR1a and Amyloid beta (Aβ), a key mediator of AD, in both the AD patients and 5xFAD mice. Changes in GHSR1a/DRD1 heteromerization and the presence of GHSR1a/Aβ complexes were accompanied by increased apoptotic neuronal death. Finally, we found that GHSR1a deficiency exacerbates hippocampal pathology in the 5xFAD mice without significantly altering Aβ production. These observations lead us to hypothesize that GHSR1a dysfunction that results from its interaction with Aβ constitute a key molecular mechanism for hippocampal synaptic injury and neuronal death, leading to cognitive impairments in AD. Here, we will determine the influence of Aβ on GHSR1a function, and we will establish the link between GHSR1a deregulation and hippocampal synaptic injury, neuronal death, and cognitive deficits in 5xFAD mice. In addition, we will address the mechanisms underlying Aβ interaction-mediated GHSR1a dysfunction. Taken together, the proposed studies will allow the causative examination of the role of GHSR1a deregulation in hippocampal pathology in AD and the evaluation of GHSR1a as a therapeutic target for AD treatment. In addition, the results can be extended to further our understanding of hippocampal pathology in other neurodegenerative diseases that involve hippocampal amyloidopathy.

阿尔茨海默病(AD)是最常见的痴呆症，以进行性认知能力下降为特征 主要针对老龄化人口。海马区突触损伤和神经变性是 阿尔茨海默病(AD)认知障碍的病理特征为了更好地理解 疾病的发病机制，以及为了改进AD的治疗方案，我们需要阐明分子 导致海马体细胞应激的机制。生长激素促分泌素受体 生长激素受体(GHSR)，也被称为Ghrelin受体，在下丘脑和海马神经元中高表达。 除了它在刺激食欲和生长激素释放方面的作用外，最近的研究还显示， GHSR的功能异构体GHSR1a在海马突触调节中的重要作用 可塑性和记忆巩固。GHSR1a与多巴胺受体d1(DRd1)异构化，因此 调节DRD1介导的突触可塑性的调节。此外，最近的研究表明，GHSR1a- 海马神经元的依赖性凋亡，表明GHSR1a在海马神经元中的关键作用 生死存亡。GHSR基因缺失的小鼠表现出类似AD样的海马区病理和认知障碍 症状。在初步研究中，我们发现GHSR1a/DRD1异构化显著减少 来自人类AD病例的海马区组织，以及在AD小鼠模型(5xFAD小鼠)中，即使 膜结合型GHSR1a和DRD1的表达水平相对保持不变。此外，我们的 初步研究揭示了GHSR1a和淀粉样β蛋白(Aβ)之间的一种意想不到的物理相互作用，这是一个关键 AD的中介物，在AD患者和5xFAD小鼠中都是如此。GHSR1a/DRD1异构化的变化和 GHSR1a/Aβ复合体的存在伴随着神经细胞凋亡率的增加。最后，我们 发现GHSR1a缺乏加剧了5xFAD小鼠的海马区病理，但没有明显的 改变β的制作。这些观察结果使我们假设GHSR1a功能障碍是由 它与Aβ的相互作用构成了海马区突触损伤和神经元死亡的关键分子机制。 导致AD患者的认知障碍。在这里，我们将确定Aβ对GHSR1a功能的影响，以及 我们将建立GHSR1a去调节与海马区突触损伤、神经元死亡和 5xFAD小鼠的认知缺陷。此外，我们还将探讨β相互作用介导的潜在机制 GHSR1a功能障碍。综上所述，拟议的研究将允许对 GHSR1a在阿尔茨海默病海马区病理中的失调节及作为治疗靶点的评价 治疗阿尔茨海默病。此外，这些结果还可以扩展到进一步了解海马区的病理学。 在其他涉及海马区淀粉样变性疾病的神经退行性疾病中。