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Therapeutic implications of purinergic receptor P2X4 in ischemic stroke

嘌呤能受体 P2X4 在缺血性中风中的治疗意义

基本信息

批准号：
10711456
负责人：
Rajkumar Verma
金额：
$ 41.47万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711456
关键词：
3xTg-AD mouse Ablation Acute Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Amyloid beta-Protein Precursor Award Behavior Behavioral Biochemical Biological Assay Brain Brain Injuries Breeding Calcium Cells Central Nervous System Cerebrovascular Disorders Cognitive Complex Data Dementia Disease Progression Elderly Exhibits Future Genetic Immune Impaired cognition Incidence Infiltration Inflammasome Inflammation Inflammatory Injury Ischemic Stroke Knock-in Knockout Mice Learning Link Macrophage Mediating Memory Microglia Molecular Morphology Mus Mutant Strains Mice Mutation Myelogenous Myeloid Cells Neurodegenerative Disorders Pathogenesis Pathway interactions Peripheral Permeability Phenotype Play Population Proteins Purinoceptor Research Role Stroke Testing Therapeutic Tissues Transgenic Mice Vascular Diseases Work attenuation behavior test cerebral atrophy cognitive change cognitive function cognitive task disease phenotype extracellular glial activation improved monocyte mouse model mutant neuroinflammation neuropathology neuroprotection pharmacologic post stroke presenilin-1 stroke recovery tau mutation young adult

项目摘要

Abstract/Summary Cerebrovascular diseases including ischemic stroke contribute to Alzheimer disease (AD) neuropathological changes, including brain atrophy and accumulation of abnormal proteins such as amyloid beta (Aβ). In the geriatric population, the incidence of dementia significantly increases after stroke. Nevertheless, the molecular links between stroke and dementia are not clearly understood but could be related to neuroinflammation. Neuroinflammation plays a key role in the pathogenesis of AD, the most prevalent form of dementia. Among the innate immune cells, brain resident microglia and infiltrated monocytes –– collectively called brain macrophages –– are the primary players in neuroinflammation. Activated brain macrophages exhibit diverse phenotypes and complex interactions during AD pathology. P2X4R, the most calcium-permeable and robust P2XR subtype present on brain macrophages, is activated by extracellular ATP. Acute activation of P2X4R on macrophages leads to inflammasome formation and thus may contribute to progressive neuroinflammation during AD progression. We previously showed that P2X4R expression and activity in myeloid cells increases swiftly and exacerbates injury after ischemic stroke. Either pharmacological inhibition or genetic deletion of P2X4R showed acute neuroprotective effects after stroke in young adult mice. P2X4R blockade reduces microglial activation and CNS infiltration of peripheral monocytes after stroke. Infiltrated monocytes from P2X4R KO mice show increased clearance of dead tissue after stroke. These data support the hypothesis that P2X4R activation of both circulating monocytes and microglia exacerbate neuroinflammation and inhibit post- stroke recovery. We will use our mouse model of myeloid cell-specific P2X4R deficiency in conjunction with 3xTG AD model to evaluate P2X4R and/or its downstream targets for the treatment of AD and AD-related dementia. In the following two aims, we want to know: 1) If P2X4R expression increases in the 3xTG AD mouse model and if its absence reduces brain damage; and 2) If deletion of P2X4R on myeloid cells improves the cognitive deficiencies that occur in AD mice with or without stroke. Regardless of the results, these simple aims will be able to identify if P2X4R plays a role in AD progression.

摘要/总结包括缺血性中风在内的脑血管疾病导致阿尔茨海默病 (AD) 神经病理学变化，包括脑萎缩和异常蛋白质（如β淀粉样蛋白（Aβ））的积累。在老年人群中，中风后痴呆症的发病率显着增加。尽管如此，分子中风和痴呆之间的联系尚不清楚，但可能与神经炎症有关。神经炎症在 AD（最常见的痴呆症）的发病机制中起着关键作用。之中先天免疫细胞、大脑驻留小胶质细胞和浸润单核细胞——统称为大脑巨噬细胞是神经炎症的主要参与者。激活的脑巨噬细胞表现出多种 AD 病理过程中的表型和复杂的相互作用。 P2X4R，钙渗透性最强、最坚固的 P2XR 亚型存在于脑巨噬细胞上，由细胞外 ATP 激活。 P2X4R 的急性激活巨噬细胞导致炎症小体形成，因此可能导致进行性神经炎症 AD 进展期间。我们之前表明，骨髓细胞中 P2X4R 的表达和活性增加迅速加剧缺血性中风后的损伤。药物抑制或基因删除 P2X4R 在年轻成年小鼠中风后表现出急性神经保护作用。 P2X4R封锁减少中风后外周单核细胞的小胶质细胞活化和中枢神经系统浸润。浸润的单核细胞来自 P2X4R KO 小鼠中风后死亡组织的清除率增加。这些数据支持以下假设：循环单核细胞和小胶质细胞的 P2X4R 激活会加剧神经炎症并抑制后遗症中风恢复。我们将使用我们的骨髓细胞特异性 P2X4R 缺陷小鼠模型 3xTG AD 模型，用于评估 P2X4R 和/或其下游靶标，用于治疗 AD 和 AD 相关疾病失智。在以下两个目标中，我们想知道： 1) 3xTG AD 中 P2X4R 表达是否增加小鼠模型以及其缺失是否会减少脑损伤； 2) 如果删除髓系细胞上的 P2X4R，症状会有所改善患有或不患有中风的 AD 小鼠中出现的认知缺陷。不管结果如何，这些简单的目标将能够确定 P2X4R 是否在 AD 进展中发挥作用。