High-Fat Diets and Memory Loss With Aging

高脂肪饮食与衰老引起的记忆丧失

• 批准号: 8536721
• 负责人: Ann-Charlotte Esther Granholm-Bentley
• 金额: $ 26.45万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536721
• 关键词: Affect; Age; Aging; Aging-Related Process; Albumins; Animals; Behavioral; Biochemical; Blood - brain barrier anatomy; Brain; Brain Stem; Cell Count; Cells; Chimera organism; Cholesterol; Cognitive; Collaborations; Data; Denervation; Development; Diet; Event; Exposure to; Fatty acid glycerol esters; Generations; Genes; Hippocampal Formation; Hippocampus (Brain); Image; Impaired cognition; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interleukin-4; Intervention; Label; Lead; Lesion; Limbic System; Lipopolysaccharides; Longevity; MRI Scans; Memory Loss; Microglia; Modeling; Monitor; Nerve Degeneration; Neurons; Outcome; Outcome Measure; Pathway interactions; Penetration; Performance; Perfusion; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Population; Predisposition; Principal Investigator; Production; Progress Reports; Public Health; Rattus; Regulation; Reporting; Research; Role; Specificity; Substantia nigra structure; System; Testing; Therapeutic; Tissue Grafts; Tissues; Toxin; age related; age related neuroinflammation; aged; aging brain; base; cytokine; density; dopaminergic neuron; fetal; frontal lobe; in vivo; locus ceruleus structure; middle age; monocyte; nerve supply; neuroinflammation; noradrenergic; normal aging; receptor; response

Aging leads to an increased susceptibility to infiammation, caused by either neuronal degeneration or external triggers, such as high-fat diets or toxins. Recent studies have suggested that some neuronal populations in the brain may act as neuroprotective entities, providing regulation at the level of microglial activation. For example, disruption of locus coeruleus (LC) -noradrenergic (NE) innervation activates microglial cells and leads to altered function of both hippocam pal neurons and dopam ine neurons of the substantia nigra (SN). Inflammatory pathways are chronically activated in the aged brain, and elevations in pro-inflammatory cytokines cause disruption of the blood-brain barrier (BBB) and lead to microglial activation. NE protection against inflammation functions by regulating the expression of inflammatory genes in the brain, and NE innervation also affects the integrity of the BBB. Degeneration of LG-NE that occurs in normal aging may therefore cause the observed inflammatory and BBB-related changes reported, but mechanisms for these events have not been examined. We propose to investigate the interaction between LG-NE loss with aging, pro-inflammatory cytokines, BBB integrity, and hippocampal-dependent memory loss. Two models are proposed: one that inflicts microglial activation by a High-fat/high cholesterol (HFHC) diet, and one model specific to the brain, using the NE selective toxin DSP-4. We believe that these two models exacerbate aging processes and can be utilized to examine specificity of NE-influence upon BBB and neuroinflammation. Reversibility of NE-degeneration induced damage will also be explored using NE- enhancing drugs. Based on our findings, we propose the following central hypothesis: BBB disruption occurring with aging is regulated by NE and contributes to age-related neuroinflammation and associated memory loss. t RELEVANCE (See instaicfe'ons): Age-related memory loss is an increasing public health problem today, due to increased longevity and the baby boomer generation. Studying basic mechanisms for this problem may lead to translational therapeutic avenues for treatment and intervention.

衰老会导致因神经元变性或 外部触发因素，例如高脂饮食或毒素。最近的研究表明一些神经元 大脑中的种群可以充当神经保护实体，在小胶质细胞水平上提供调节 激活。例如，破坏层基因座（LC） - 非肾上腺素能（NE）神经激活 小胶质细胞并导致河马PAL神经元和多巴糖神经元的功能改变 黑质尼格拉（SN）。炎症途径在老年大脑中长期激活，并在 促炎性细胞因子会导致血脑屏障（BBB）破坏并导致小胶质细胞 激活。通过调节炎症基因的表达来防止炎症功能 在大脑中，NE神经也会影响BBB的完整性。 LG-NE的变性发生在 因此，正常衰老可能会导致观察到的炎症和BBB相关的变化报告，但 这些事件的机制尚未检查。我们建议研究 衰老，促炎细胞因子，BBB完整性和海马依赖性记忆丧失的LG-NE损失。 提出了两种模型：一种通过高脂/高胆固醇（HFHC）饮食造成小胶质细胞激活的模型， 使用NE选择性毒素DSP-4，一种特定于大脑的模型。我们相信这两个模型 恶化的衰老过程，可用于检查BBB和BBB和 神经炎症。还将使用NE-还将探索NE降级诱导损伤的可逆性 增强药物。根据我们的发现，我们提出以下中心假设：BBB破坏 衰老的发生受NE的调节，并有助于与年龄有关的神经炎症和相关 记忆丧失。 t 相关性（请参阅Instaicfe'ons）： 由于寿命的增加和 婴儿潮一代。研究此问题的基本机制可能会导致转化治疗 治疗和干预的途径。