High-Fat Diets and Memory Loss With Aging

衰老导致对感染的敏感性增加，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，一些神经元 大脑中的群体可能作为神经保护实体，在小胶质细胞水平上提供调节 激活。例如，破坏蓝斑(LC)-去甲肾上腺素(NE)神经支配激活 小胶质细胞，并导致海马PAL神经元和多巴胺神经元功能改变。 黑质(SN)。炎症通路在老年人的大脑中被慢性激活，而在 促炎细胞因子导致血脑屏障(BBB)的破坏并导致小胶质细胞 激活。NE通过调节炎症基因的表达发挥抗炎作用 在大脑中，NE神经支配也影响血脑屏障的完整性。Lg-NE的退变发生在 因此，正常衰老可能会导致观察到的炎症和与血脑屏障相关的变化，但 这些事件的机制还没有被研究过。我们建议研究两者之间的互动 衰老、促炎细胞因子、血脑屏障完整性和海马区依赖记忆丧失导致的LG-NE丢失。 提出了两种模型：一种是通过高脂肪/高胆固醇(HFHC)饮食引起的小胶质细胞激活， 一种是针对大脑的模型，使用NE选择性毒素DSP-4。我们认为这两种模式 可加速衰老过程，可用于检查NE对血脑屏障和 神经炎。NE-退行性损伤的可逆性也将用NE- 加强药物的使用。基于我们的发现，我们提出了以下中心假设：血脑屏障紊乱 与衰老有关的发生受去甲肾上腺素调节，并有助于与年龄相关的神经炎症和相关 失忆。 T 相关性(参见Instaicfe‘ONS)： 与年龄相关的记忆力丧失是当今一个日益严重的公共健康问题，这是由于寿命的延长和 婴儿潮一代。研究这个问题的基本机制可能导致转化性治疗 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.