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: 10266217
• 负责人: Heng Du
• 金额: $ 45.18万
• 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/10266217
• 关键词: GHSR1a; Hippocampal; Pathology; Alzheimer; Disease

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（Alzheimer's disease，AD）是最常见的痴呆类型，其特征是进行性认知功能下降 主要针对老龄化人口。海马突触损伤和神经退行性变 阿尔茨海默病（AD）认知功能障碍的病理特征。为了更好地理解 疾病的发病机制，并改善AD的治疗方案，我们需要阐明的分子 导致海马体细胞压力的机制。生长激素促分泌素受体 生长激素释放肽受体（GHSR），也称为生长激素释放肽受体，在下丘脑和海马的神经元中高度表达。 除了刺激食欲和生长激素释放的作用外，最近的研究表明， GHSR 1a是GHSR的功能亚型，在调节海马突触中的重要作用 可塑性和记忆巩固。GHSR 1a与多巴胺受体D1（DRD 1）异聚化，因此 调节DRD 1介导的突触可塑性调节。此外，最近的研究表明，GHSR 1a- 海马神经元依赖性凋亡，表明GHSR 1a在海马神经元凋亡中的关键作用。 生存GHSR缺失小鼠表现出类似AD样的海马病理学和认知障碍 症状在初步的研究中，我们发现在哺乳动物中GHSR 1a/DRD 1异聚化显著减少。 来自人类AD病例的海马组织，以及AD小鼠模型（5xFAD小鼠），即使 膜结合GHSR 1a和DRD 1的表达水平保持相对不变。另外我们 初步研究揭示了GHSR 1a和淀粉样蛋白β（Aβ）之间意想不到的物理相互作用， 在AD患者和5xFAD小鼠中，GHSR 1a/DRD 1异聚化的变化和GHSR 1a/DRD 1基因的表达 GHSR 1a/Aβ复合物的存在伴随着神经元凋亡的增加。最后我们 发现GHSR 1a缺乏会加重5xFAD小鼠的海马病理学， 改变Aβ的产生。这些观察使我们假设GHSR 1a功能障碍是由以下原因引起的： 它与Aβ相互作用构成了海马突触损伤和神经元死亡的关键分子机制， 导致AD的认知障碍。在这里，我们将确定Aβ对GHSR 1a功能的影响， 我们将建立GHSR 1a失调与海马突触损伤、神经元死亡和 5xFAD小鼠的认知缺陷。此外，我们还将探讨Aβ相互作用介导的 GHSR 1a功能障碍。总之，拟议的研究将允许因果审查的作用， GHSR 1a在AD海马病理学中的失调及其作为治疗靶点的评价 治疗AD。此外，该结果可以扩展到进一步我们对海马病理学的理解 海马淀粉样变性等神经退行性疾病中的作用。