The role of NMDA receptor subunit GluN3A in age and Alzheimer's disease-related dementia

NMDA 受体亚基 GluN3A 在年龄和阿尔茨海默病相关痴呆中的作用

• 批准号: 10491045
• 负责人: Shan P. Yu
• 金额: $ 19.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491045
• 关键词: AD transgenic mice; Acetylcholinesterase Inhibitors; Adolescent; Adult; Affect; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Anxiety; Apoptosis; Astrocytes; Axon; Behavior; Biological Assay; Brain; Brain region; CASP3 gene; Cell Death; Cells; Chronic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Cognitive; Cognitive deficits; Data; Dementia; Dementia with Lewy Bodies; Dendrites; Deterioration; Development; Disease; Disease Progression; Dose; Early treatment; Embryo; Ensure; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Frontotemporal Dementia; Functional disorder; Future; Genes; Genetic; Glial Fibrillary Acidic Protein; Glutamates; Goals; Health; Hippocampus (Brain); Homeostasis; Housing; Human; Impaired cognition; Impairment; In Situ Nick-End Labeling; Incidence; Inflammatory; Interleukins; Intervention; Investigation; Knock-out; Knockout Mice; Knowledge; Label; Learning; Measures; Mediating; Memantine; Memory; Microglia; Mus; N-Methyl-D-Aspartate Receptors; N-methyl-D-glutamate; NMDA receptor A1; Neocortex; Neonatal; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathology; Patients; Peptides; Personality; Persons; Pharmacology; Phenotype; Physiological; Play; Process; Quality of life; Reaction; Regulation; Reporting; Research; Rodent; Role; Senile Plaques; Structure; Symptoms; Synapses; TNF gene; Testing; Therapeutic; Time; Vascular Dementia; Virulence Factors; Western Blotting; Wild Type Mouse; Work; abeta deposition; age related; antagonist; base; clinical diagnosis; clinical investigation; clinical translation; conditional knockout; death anxiety; disease phenotype; evidence base; excitotoxicity; experimental study; extracellular; hyperphosphorylated tau; loss of function; middle age; mouse model; neuron loss; neuropathology; new therapeutic target; normal aging; postnatal; pre-clinical; preclinical study; prevent; receptor; tau Proteins; tau phosphorylation; theories; young adult

Summary Dementia and Alzheimer’s disease (AD) affect hundreds of millions of people in the US and worldwide, after several decades of intensive investigations clinical treatments of these age-related disorders are still very limited. Previous investigations using animal models established on the amyloid beta (Aβ) and Tau hypothesis have helped to gain extensive knowledge on the pathological features and progression of AD related dementia. Unfortunately, clinical trials directly targeting Aβ and Tau pathology have so far failed clinical translation. On the other hand, hyperactivation of N-Methyl-D-aspartate receptors (NMDARs) has been identified as a key mechanism contributing to AD pathology and pathogenesis. The NMDAR antagonist memantine is one of few treatments showing some therapeutic benefits for moderate/severe AD and dementia patients. In fact, pharmacological suppression of glutamatergic activities has become an important strategy in postponing Aβ- induced neuronal damage and AD progression. The research in NMDAR regulations, however, has been heavily focused on the NMDAR subunits GluN1 and GluN2, there is no information about the role of GluN3A in AD related mechanism. As a unique inhibitory subunit of NMDARs, GluN3 keeps the tonic NMDAR activity and chronic Ca2+ homeostasis within the physiological range. Deletion of GluN3A in the knockout (KO) mouse resulted in enhanced neuronal cell death and anxiety behaviors at adult ages. Our preliminary data show that GluN3A KO mice undergo spontaneous evolvement of AD-like pathology and cognitive deficits with aging, which can be prevented by daily treatments of low-dose memantine initiated from the pre-onset stage. In this R21 investigation, we will verify the pathogenic role of GluN3A in age-dependent manners. Specific Aim 1 will characterize the pathological features of the age-dependent dementia and the relation to Alzheimer’s disease. In GluN3A KO and WT mice of different ages, we will examine Aβ plagues, NFT, phosphorylation of Tau protein, synaptic structures and cell death in the hippocampus and cortex. Inflammatory reactions including reactive astrocytes, microglia/microphage, and inflammatory factors will be measure. Specific Aim 2 will delineate the critical time window for the role of GluN3A in progression of AD-associated pathophysiology. We will perform loss-of-function experiments of conditional GluN3A knockout at different ages to understand whether there is a critical time point for initiating the age-dependent evolvement of dementia and AD pathophysiology. This R21 investigation is the first effort in revealing a regulatory/pathogenic role of the NMDAR subunit GluN3A in age-related dementia and possibly a sporadic AD mouse model. This exploratory study will allow us to develop an evidence-based systematic investigation on the GluN3A-regulated mechanism of dementia and AD pathology. Our ultimate goal is to identify GluN3A as a novel therapeutic target and develop early genetic and pharmacological interventions for an optimal NMDAR regulation in order to delay or even prevent the gradually evolved dementia and the progression of AD pathophysiology.

总结 痴呆症和阿尔茨海默病（AD）影响美国和全世界数亿人， 经过几十年的深入研究，这些与年龄有关的疾病的临床治疗仍然非常困难。 有限公司先前使用基于淀粉样蛋白β（Aβ）和Tau假说建立的动物模型进行的研究 有助于获得有关AD相关痴呆的病理特征和进展的广泛知识。 不幸的是，直接靶向Aβ和Tau病理学的临床试验迄今未能实现临床转化。对 另一方面，N-甲基-D-天冬氨酸受体（NMDARs）的超活化已被确定为 有助于AD病理和发病机制的机制。NMDAR拮抗剂美金刚是少数 治疗显示出对中度/重度AD和痴呆患者的一些治疗益处。事实上， 药理学上抑制Aβ-受体激动剂的活性已成为延缓Aβ-受体阻滞剂的重要策略。 引起神经元损伤和AD进展。然而，对NMDAR法规的研究一直是 由于主要集中在NMDAR亚基GluN 1和GluN 2上，没有关于GluN 3A在 AD相关机制。GluN 3作为NMDARs的一个独特的抑制性亚基，保持了NMDAR的活性， 生理范围内的慢性Ca 2+稳态。敲除（KO）小鼠中GluN 3A的缺失 导致成年时神经细胞死亡和焦虑行为的增加。初步数据显示， GluN 3A KO小鼠经历AD样病理和认知缺陷随年龄增长的自发演变， 这可以通过从发病前阶段开始的低剂量美金刚的每日治疗来预防。在这 R21调查，我们将验证GluN 3A在年龄依赖性方式的致病作用。具体目标1将 描述年龄依赖性痴呆的病理特征及其与阿尔茨海默病的关系 疾病在不同年龄的GluN 3A KO和WT小鼠中，我们将检测Aβ斑块、NFT、 海马和皮层中的Tau蛋白、突触结构和细胞死亡。炎症反应 包括反应性星形胶质细胞、小胶质细胞/小噬菌体和炎症因子。具体目标2 将描绘GluN 3A在AD相关性进展中作用的关键时间窗。 病理生理学我们将在不同的条件下进行条件性GluN 3A敲除的功能丧失实验。 年龄，以了解是否有一个关键的时间点，启动年龄依赖的演变， 痴呆和AD病理生理学。这项R21调查是首次努力揭示一种调节性/致病性 NMDAR亚基GluN 3A在年龄相关性痴呆和可能的散发性AD小鼠模型中的作用这 探索性研究将使我们能够对GluN 3A调节的 痴呆机制和AD病理学。我们的最终目标是确定GluN 3A作为一种新的治疗药物， 针对并开发早期遗传和药物干预措施，以实现最佳NMDAR调节， 延缓甚至预防逐渐发展的痴呆和AD病理生理学的进展。