Aging exacerbates trauma-induced immune pathways and neuronal dysfunction

衰老加剧创伤引起的免疫途径和神经元功能障碍

基本信息

批准号：
9924452
负责人：
Susanna Rosi
金额：
$ 35.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924452
关键词：
Acute Affect Age Aging Alzheimer&apos s Disease Animals Behavioral Brain Brain Diseases Brain Injuries Cells Chronic Clinical Clinical Trials Cognition Cognitive Cognitive deficits Communities Complement Complement Activation Data Dementia Dendrites Dendritic Spines Dependovirus Development Elderly Environmental Risk Factor Enzymes Event Evolution Functional disorder Future Genetic Models Goals Hippocampus (Brain)Human Immune Impaired cognition Incidence Individual Infiltration Inflammation Inflammatory Inflammatory Response Injections Injury Innate Immune Response Innate Immune System Kinetics Label Lead Ligands Link Long-Term Effects Measures Mediating Microglia Morbidity - disease rate Morphology Mus Myeloid Cells Nerve Degeneration Nervous System Physiology Neuronal Dysfunction Neurons Outcome Pathway interactions Peripheral Pharmacology Play Population Production Prognostic Factor Reactive Oxygen Species Reporter Research Research Design Risk Role Severities Structure Superoxides Synapses System TBI treatment Testing Time Trauma Traumatic Brain Injury United States Viral Work aging brain aging population base brain parenchyma clinically relevant cognitive function dementia risk density effective therapy high risk improved inflammatory milieu innovation macrophage mild traumatic brain injury monocyte mortality mouse model neuroinflammation neurotoxic neurotoxicity older patient preclinical study preservation prevent recruit response synaptic function synaptic pruning therapeutic target treatment strategy

项目摘要

Project Summary Traumatic brain injury (TBI) is extremely debilitating for the aging community with both increased incidence and outcome severity within this population. Furthermore, TBI is a strong environmental risk factor for development of Alzheimer's disease and other dementia related illnesses. The importance of age as a prognostic factor after TBI has long been recognized but limited studies have been devoted to understand mechanisms that regulate secondary events that occur after the initial trauma. Even less research has been aimed at studying the mechanisms of cognitive loss in the elderly. The critical changes that affect cognition take place over a long period of time following the initial insult and the innate immune system activation is a key secondary injury mechanism that contributes to chronic neurodegeneration and loss of neurological function. In this proposal we will investigate the respective contribution of infiltrating macrophages and activated resident microglia in production of a neurotoxic and inflammatory milieu as well as direct interactions with neuronal synapses following TBI in an aging animal. Preliminary data for this proposal has found that TBI causes an exacerbated and prolonged CCR2+ macrophage infiltration in the aging brain. The increased recruitment of peripherally derived monocytes significantly augments TBI-induced neuroinflammatory sequelae and is paralleled by an increased expression of the superoxide-generating enzyme NOX2 which may potentiate injury-induced cognitive dysfunction observed in old animals. All together these findings demonstrate that, in the aging brain, peripherally derived macrophages have a distinct contribution to the TBI-related inflammatory response. Based upon these observations we hypothesize that the robust infiltration of peripherally derived macrophages and the consequent inflammatory response is responsible for exacerbated loss of cognitive functions by decreasing dendritic spine density. In this proposal, we will identify the temporal relationships between macrophage infiltration/microglia activation and inflammatory profiles in an aging brain after injury. Furthermore, we will identify mechanistic links between macrophage infiltration and altered dendritic spine morphology. We will determine if TBI-induced cognitive deficits are a direct result of macrophage induced ROS production and/or inappropriate synaptic pruning. Finally, we will investigate if blockade of macrophage infiltration can mitigate injury-induced neurotoxicity thereby alleviating cognitive deficits. Findings from this work will advance mechanistic understanding of secondary mechanisms associated with TBI and test two pharmacological agents (already in clinical trials) for treatment of TBI-induced cognitive deficits in an aging animal.

项目摘要创伤性脑损伤（TBI）对于衰老社区的发病率和结果严重程度。此外，TBI是发展的强大环境风险因素阿尔茨海默氏病和其他与痴呆症有关的疾病。年龄作为预后因素的重要性长期以来，TBI已被认可，但有限的研究一直致力于了解调节的机制初始创伤后发生的次要事件。甚至较少的研究旨在研究老年人认知丧失的机制。影响认知的关键变化发生了很长的时间初始侮辱和先天免疫系统激活后的时间段是关键的次要伤害有助于慢性神经退行性的机制和神经功能的丧失。在这个建议中，我们将研究浸润巨噬细胞和活化的居民小胶质细胞的各自贡献产生神经毒性和炎症环境以及与神经元突触的直接相互作用在衰老的动物中进行TBI。该提案的初步数据发现TBI导致恶化并长时间的CCR2+巨噬细胞在衰老的大脑中浸润。外围招募的增加衍生的单核细胞显着增强了TBI诱导的神经炎性后遗症，并与增加了可能增强损伤诱导的超氧化物生成酶NOX2的表达在老动物中观察到认知功能障碍。所有这些发现都表明，在大脑衰老中，外围衍生的巨噬细胞对与TBI相关的炎症反应有明显的贡献。基于这些观察结果，我们假设周围衍生的巨噬细胞的稳健浸润随之而来的炎症反应是导致通过树突状脊柱密度降低。在此提案中，我们将确定巨噬细胞浸润/小胶质细胞激活和受伤后衰老大脑的炎症特征。此外，我们将确定巨噬细胞浸润和树突状脊柱改变之间的机械联系形态学。我们将确定TBI诱导的认知缺陷是否是巨噬细胞诱导的ROS的直接结果生产和/或不适当的突触修剪。最后，我们将研究巨噬细胞的封锁浸润可以减轻损伤引起的神经毒性，从而减轻认知缺陷。从中的发现工作将提高对与TBI相关的二级机制的机械理解和测试。药理学剂（已经在临床试验中）用于治疗衰老的TBI诱导认知缺陷动物。