Project 2: Synergy of ABeta clearance mechanisms in vivo

β多肽在大脑中的积累似乎引发了疾病的发生，并导致了许多 与阿尔茨海默病(AD)相关的认知和行为症状。其他病理学，如 作为神经原纤维缠结的过度磷酸化的tau和作为路易小体的α-突触核蛋白(α-syn)也是 在AD中是有害的。而路易小体最为人所知的是聚集在帕金森氏症的纹状体内 疾病，60%的AD患者也存在类似的α-SYN结构。鉴于Aβ和α-syn 病理通常是共存的，我们的目标是了解这两种多肽的复杂生物学以及它们是如何 相互作用，影响AD的发展和进展。β通常在神经元中产生并分泌 进入脑细胞外液或间质液，这是形成寡聚体和β的一个来源 斑块。A-β从其正常的可溶性形式转化为这些有毒构象是浓度依赖的； 高水平的Aβ比低浓度的Aβ更容易聚集。一种平衡 Aβ的产生和消除之间的关系决定了Aβ在大脑中的稳态浓度。Aβ级别 在AD中急剧上升，表明在患病的人中，至少有一个代谢过程被破坏 大脑。最近的研究有力地表明，导致AD大脑中β积聚的一个关键因素是缺陷 来清除大脑中的多肽。参与从大脑清除活性Aβ的几种机制有 如1)蛋白质降解，2)细胞摄取，3)跨血脑主动运输 障碍。虽然这些清除途径同时起作用将Aβ从大脑中移除，但 目前还不清楚每种机制是独立运行、竞争还是合作。许多研究都有 专注于每种机制如何单独清除β，但很少有人确定这些机制是如何 各种机制在协同中发挥作用。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。总体而言，我们假设Aβ和α-SYN的清除不是单独发生的，而是 既受一系列机制的影响，也受彼此的影响。我们将确定这些途径是如何相互作用的 通过一次阻断一个或多个机制并测量β的比率来清除大脑中的β 来自ISF的许可。我们还将确定这些清除路径在设置中的功能差异 联合病理(α-SYN和Aβ)。

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).