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Systemic inflammation in regulating the onset and progression of brain aging

全身炎症调节大脑衰老的发生和进展

基本信息

批准号：
9915827
负责人：
THOMAS C FOSTER
金额：
$ 37.5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915827
关键词：
Age Age-associated memory impairment Aging Alzheimer&apos s Disease Animals Anti-Inflammatory Agents Antiinflammatory Effect Antioxidants Apoptotic Behavior Behavioral Brain Brain region Cells Chronic Cognition Cognitive aging Data Dementia Development Diagnostic Encephalitis Executive Dysfunction Female Gene Expression Genes Genetic Transcription Goals Health Immune Impaired cognition Impairment In Vitro Inflammation Injections Interleukin-6 Intramuscular Injections Link Lipopolysaccharides Measures Medial Mediating Memory Memory impairment Methods Microglia Modeling Motivation Motor Muscle N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurons Oxidation-Reduction Oxidative Stress Performance Peripheral Pharmaceutical Preparations Phenotype Prefrontal Cortex Publishing Rattus Reaction Time Reactive Oxygen Species Regulation Role Serum Sex Differences Specificity Stress Synapses Synaptic Receptors Synaptic plasticity System Testing Up-Regulation Viral Viral Vector Virus Work age related age related neurodegeneration aged aging brain antioxidant enzyme astrogliosis base behavior measurement behavior test biological adaptation to stress cell type cognitive function cognitive process cytokine executive function glial activation inflammatory marker male middle age motor impairment next generation sequencing novel preservation public health relevance receptor function relating to nervous system selective expression senescence stressor synaptic function vigilance

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed work is to provide an understanding the role of chronic inflammation in the onset and progression of cognitive decline during aging and Alzheimer's disease. Impaired memory, an early indicator of cognitive decline, is due to impaired synaptic function associated with a redox-mediated hypofunction of N-methyl-D-aspartate receptors (NMDARs). The mechanism involves reactive oxygen species (ROS), possibly from activated microglia, providing a potential link between inflammation and the emergence of impaired memory. Aim 1 will test the hypothesis that the onset of cognitive decline is influenced by an inflammation induced increase in oxidative stress, resulting in a redox-mediated NMDAR hypofunction. Studies employ sensitive behavioral tests for different cognitive processes, and can detect changes in motor function or motivation. Impaired cognitive function will be related to measures of serum and local brain cytokines, glial activation, oxidativ stress, and redox regulation of NMDAR function. We predict that inflammatory markers in the serum are predictive of the emergence of memory deficits and that for specific neural systems, inflammation markers, and impaired NMDAR function is diagnostic of different cognitive impairment phenotypes. Evidence indicates that decreased NMDAR synaptic activity results in transcriptional changes similar to that associated with age-related cognitive decline and Alzheimer's disease suggesting that a decrease in NMDAR synaptic activity, due to chronic inflammation, alters transcription of neurotrophic, neuroprotective, and synapse specific genes. Aim 2 examines brain transcription and cognitive decline due to chronic low-level of systemic inflammation. A systemic inflammation model has been developed and involves muscle expression of interleukin-6 (IL-6), which elevates serum IL-6 and induces brain astrogliosis and microglia activation. We predict that a long-term (3 months) increase in serum cytokines will result in a redox-mediated NMDAR hypofunction and a senescent transcription profile. Aim 3 will examine the idea that region selective upregulation of antioxidant enzymes will have a selective effect in protecting NMDAR function, promoting a youthful transcriptional profile, and rescuing cognition.