Project 2: Synergy of ABeta clearance mechanisms in vivo

Aβ肽在脑中的积累似乎启动了疾病的发作，并导致许多脑损伤。 与阿尔茨海默病（AD）相关的认知和行为症状。其他疾病，如 作为神经元缠结的过度磷酸化的tau蛋白和作为路易体的α-突触核蛋白（α-syn）也被 不利于AD。虽然路易体是最有名的积累在纹状体内帕金森氏症 在AD疾病中，60%的AD病例中存在同样由α-syn组成的类似结构。假设Aβ和α-syn 病理学往往共存，我们的目标是了解这两种肽的复杂生物学，以及它们如何 相互作用，影响AD的发展和进程。Aβ通常在神经元中产生并分泌 进入脑细胞外液或间质液（ISF），这是Aβ的一种来源，A β形成寡聚体， 斑块Aβ从其正常可溶性形式转化为这些毒性构象是浓度依赖性的; 高浓度Aβ比低浓度Aβ更容易聚集。平衡 Aβ生成和消除之间的关系决定了Aβ在脑中的稳态浓度。Aβ水平 在AD中显著升高，表明至少有一种代谢过程在患病的人中被破坏。 个脑袋最近的研究强烈表明，导致AD脑中Aβ积聚的一个关键因素是缺陷 清除大脑中的肽。参与脑内Aβ活性清除的几种机制， 已经确定，如1）蛋白水解降解，2）细胞摄取，和3）通过血脑的主动运输 屏障虽然这些清除途径同时起作用以从大脑中清除Aβ，但A β的清除程度与A β的清除程度有关。 每个机制是独立工作，竞争还是合作仍然不清楚。许多研究 这些机制中的每一种如何单独清除Aβ，然而很少有人确定这些机制是如何清除Aβ的。 机制协同工作。有趣的是，这些清除途径中的一些似乎作用于Aβ以及 α-突触核蛋白。总之，我们假设Aβ和α-syn的清除不是孤立发生的，而是 受到一系列机制的影响，也受到彼此的影响。我们将确定这些途径如何相互作用 通过一次阻断一种或多种机制并测量Aβ的速率， 安全部队的许可我们还将确定这些清除途径在环境中的功能差异 α-syn和Aβ的联合病理。

Accumulation of Aβ peptide in the brain appears to initiate disease onset and causes of many of the cognitive and behavioral symptoms related to Alzheimer’s disease (AD). Other pathologies such as hyperphosphorylated tau as neurofibrillary tangles and α-synuclein (α-syn) as Lewy Bodies are also detrimental in AD. While Lewy Bodies are best known for accumulation within the striatum in Parkinson’s disease, similar structures also composed of α-syn are present in 60% of AD cases. Given that Aβ and α-syn pathologies often co-exist, our goal is to understand the complex biology of both peptides and how they interact to influence the development and progression of AD. Aβ is normally produced in neurons and secreted into the brain extracellular fluid, or interstitial fluid (ISF), which is one source of Aβ that forms oligomers and plaques. Conversion of Aβ from its normal soluble form into these toxic conformations is concentrationdependent; high levels of Aβ are much more prone to aggregate than lower concentrations of Aβ. A balance between Aβ generation and elimination determines the steady-state concentration of Aβ in the brain. Aβ levels rise dramatically in AD, suggesting that at least one of these metabolic processes is disrupted in the diseased brain. Recent studies strongly suggests that a key factor leading to Aβ accumulation in the AD brain is a defect in clearing the peptide from the brain. Several mechanisms involved in active Aβ clearance from the brain have been identified, such as 1) proteolytic degradation, 2) cellular uptake, and 3) active transport across the bloodbrain barrier. While these clearance pathways work simultaneously to remove Aβ from the brain, the degree to which each mechanism works independently, competes, or cooperates remains unclear. Many studies have focused on how each of these mechanisms individually clear Aβ, however few have determined how these mechanisms work in synergy. Interestingly, some of these clearance pathways appear to act on Aβ as well as α-synuclein. Overall, we hypothesize that clearance of Aβ and α-syn does not occur in isolation, but instead is influenced by an array of mechanisms as well as by each other. We will identify how these pathways interact to clear Aβ from the brain by blocking one or more mechanism at a time and measuring the rate of Aβ clearance from the ISF. We will also determine differences in function of these clearance pathways in settings of combined pathology (α-syn and Aβ).