High-Fat Diets and Memory Loss With Aging

衰老导致对炎症的易感性增加，这是由神经元变性或 外部诱因，如高脂饮食或毒素。最近的研究表明， 脑中的神经细胞群可以作为神经保护实体，在小胶质细胞水平上提供调节， activation.例如，蓝斑（LC）-去甲肾上腺素（NE）神经支配的中断激活了 小胶质细胞，并导致改变的功能，这两个突触pal神经元和多巴胺神经元的 黑质（SN）。炎症通路在老年大脑中被慢性激活， 促炎细胞因子引起血脑屏障（BBB）的破坏并导致小胶质细胞增生。 activation. NE通过调节炎症基因的表达发挥抗炎作用 NE神经支配也影响BBB的完整性。LG-NE变性发生在 因此，正常的衰老可能会导致所观察到的炎症和BBB相关的变化，但 这些事件的机制尚未研究。我们建议调查之间的相互作用 LG-NE损失与老化，促炎细胞因子，血脑屏障的完整性，和海马依赖性记忆丧失。 提出了两种模型：一种是通过高脂肪/高胆固醇（HFHC）饮食引起小胶质细胞活化， 和一种使用NE选择性毒素DSP-4的脑特异性模型。我们认为这两个模型 加剧老化过程，并可用于检查NE对BBB影响的特异性， 神经炎症NE变性诱导的损伤的可逆性也将使用NE- 增强药物。基于我们的研究结果，我们提出了以下中心假设： 随着年龄的增长，NE调节并有助于与年龄相关的神经炎症和相关的 失忆 不 相关性（见说明）： 由于寿命的延长和疾病的发展，与记忆有关的记忆丧失是当今日益严重的公共卫生问题。 婴儿潮一代研究这个问题的基本机制可能会导致转化治疗 治疗和干预的途径。

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.