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: 9918235
• 负责人: Heng Du
• 金额: $ 1.11万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 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 2020-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918235
• 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) 的特点是进行性认知能力下降，是最常见的痴呆症类型 主要攻击人口老龄化的海马突触损伤和神经退行性疾病。 阿尔茨海默病（AD）认知缺陷的病理特征，以便更好地了解。 该疾病的发病机制，并改善AD治疗方案，我们需要阐明其分子机制 导致海马细胞应激的机制生长激素促分泌受体。 (GHSR)，也称为生长素释放肽受体，在下丘脑和海马的神经元中高表达。 除了刺激食欲和释放生长激素外，最近的研究还表明， GHSR1a（GHSR 的功能亚型）在海马突触调节中的重要贡献 GHSR1a 与多巴胺受体 D1 (DRD1) 异聚，从而实现可塑性和记忆巩固。 此外，最近的研究表明 GHSR1a- 调节 DRD1 介导的突触可塑性。 海马神经元依赖性凋亡，表明 GHSR1a 在海马神经元中的关键作用 GHSR 缺失小鼠表现出类似于 AD 样的海马病理学和认知障碍。 在初步研究中，我们发现 GHSR1a/DRD1 异聚化显着减少。 来自人类 AD 病例以及 AD 小鼠模型（5xFAD 小鼠）的海马组织，尽管 膜结合 GHSR1a 和 DRD1 的表达水平保持相对不变。 初步研究揭示了 GHSR1a 和β淀粉样蛋白 (Aβ) 之间意想不到的物理相互作用，Aβ 是 AD 患者和 5xFAD 小鼠中 GHSR1a/DRD1 异聚化和 GHSR1a/Aβ复合物的存在伴随着神经元凋亡的增加。 发现 GHSR1a 缺乏会恶化 5xFAD 小鼠的海马病理，但没有显着影响 这些观察结果使我们发现 GHSR1a 功能障碍是由 GHSR1a 引起的。 它与 Aβ 的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 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 失调与海马突触损伤、神经元死亡和 此外，我们将探讨 Aβ 相互作用介导的潜在机制。 综上所述，拟议的研究将有助于对 GHSR1a 功能障碍的作用进行病因检查。 AD 海马病理学中 GHSR1a 的失调以及 GHSR1a 作为治疗靶点的评估 此外，该结果还可以进一步扩展我们对海马病理学的理解。 涉及海马淀粉样变性的其他神经退行性疾病。