GHSR1a and Hippocampal Pathology in Alzheimer's Disease

阿尔茨海默病中的 GHSR1a 和海马病理学

基本信息

批准号：
10393665
负责人：
Heng Du
金额：
$ 45.2万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393665
关键词：
Abeta synthesis Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

以进行性认知能力下降为特征主要攻击老龄化人口。海马合成损伤和神经变性正在定义阿尔茨海默氏病（AD）认知缺陷的病理特征。为了更好地了解疾病的发病机理，为了改善AD治疗选择，我们需要阐明分子引起海马的细胞应激的机制。成长马的秘密接收者（GHSR），也称为生长素受体，在下丘脑和海马的神经元中高度表达。除了它在刺激食欲和生长马释放中的作用外，最近的研究表明 GHSR1A（GHSR的功能同工型）在海马突触的调节中的重要贡献可塑性和记忆合并。 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存。 GHSR无效小鼠暴露了海马病理学和类似于广告的认知障碍症状。在初步研究中，我们发现GHSR1A/DRD1异构化大大降低了来自人类AD病例的海马组织以及AD小鼠模型（5XFAD小鼠），即使膜结合的GHSR1A和DRD1的表达水平保持相对保留。另外，我们的初步研究表明，GHSR1A和淀粉样β（Aβ）之间存在意外的物理相互作用（钥匙） AD患者和5XFAD小鼠的AD介体。 GHSR1A/DRD1异构化的变化和通过增加凋亡神经元死亡来实现GHSR1A/Aβ复合物的存在。最后，我们发现GHSR1A缺乏加剧了5xFAD小鼠的海马病理改变Aβ产生。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，并确定我们将建立GHSR1A放松管制与海马突触损伤，神经元死亡和认知定义了5xFAD小鼠。此外，我们将解决Aβ相互作用介导的机制 GHSR1A功能障碍。综上所述，拟议的研究将允许对 AD中海马病理学中的GHSR1A放松管制，并评估GHSR1A作为治疗靶标用于广告处理。此外，可以扩展结果以进一步了解海马病理在其他涉及海马淀粉样病的神经退行性疾病中。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Type I interferon response-related microglial Mef2c deregulation at the onset of Alzheimer's pathology in 5×FAD mice.

DOI：
10.1016/j.nbd.2021.105272
发表时间：
2021-05
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Xue F;Tian J;Yu C;Du H;Guo L
通讯作者：
Guo L

TREM2 Mediates Microglial Anti-Inflammatory Activations in Alzheimer's Disease: Lessons Learned from Transcriptomics.

DOI：
10.3390/cells10020321
发表时间：
2021-02-04
期刊：
Cells
影响因子：
6
作者：
Xue F;Du H
通讯作者：
Du H

Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer's Disease.

DOI：
10.3390/cells10030649
发表时间：
2021-03-15
期刊：
Cells
影响因子：
6
作者：
Jia K;Du H
通讯作者：
Du H

Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination.

DOI：
10.1038/s41598-020-74613-9
发表时间：
2020-10-16
期刊：
Scientific reports
影响因子：
4.6
作者：
Chen H;Tian J;Guo L;Du H
通讯作者：
Du H

Modulation of OSCP mitigates mitochondrial and synaptic deficits in a mouse model of Alzheimer's pathology.

DOI：
10.1016/j.neurobiolaging.2020.09.018
发表时间：
2021-03
期刊：
Neurobiology of aging
影响因子：
4.2
作者：
Gauba E;Sui S;Tian J;Driskill C;Jia K;Yu C;Rughwani T;Wang Q;Kroener S;Guo L;Du H
通讯作者：
Du H