Blood Brain Barrier Dysfunction in Parkinson's Diseases

惯例表明，除非存在特定的转运机制，血脑屏障（BBB）可阻止某些药物和神经毒素进入帕金森病（PD）患者的多巴胺（DA）神经元。然而，我们在动物、体外和尸体解剖研究中发现，PD模型和患者的BB功能失调。动物和体外研究表明，活化的小胶质细胞产物是造成这种功能障碍的原因。如果barri功能受损，大脑将暴露在外周血管中的元素。我们假设血脑屏障功能障碍会导致脑实质暴露于血液中的DA神经毒素以及外周免疫系统介质（T细胞和单核细胞），这将有助于疾病进展。目的：II评估预先存在DA病变（由MPTP和LPS诱导）的小鼠的进行性DA神经元损失，以证明氚标记的、系统性给药的DA神经毒素（MPP+）和免疫介质的进入增加。目的2将评估来自活化小胶质细胞（细胞系和从DA损伤小鼠中分离的小胶质细胞）的片段对内皮细胞（EC）单层（人细胞系和小鼠引物培养）的影响，以及DA毒素运输的变化以及免疫介质的迁移。这些研究还将确定产生血脑屏障的紧密连接中的蛋白质和超微结构变化（EM研究）。我们预计这些研究将表明，神经炎症介导的事件会影响紧密连接中的蛋白结构，破坏血脑屏障，导致血管周围血管元素进入，从而导致进一步的DA神经元损失和疾病进展。这些发现将首次系统地证明PD动物模型中存在屏障功能，并确定这种功能的潜在机制。这些发现将为先天性进展提供一个全新的假设，并确定围绕影响血脑屏障完整性设计的PD治疗干预的新靶点。

Convention suggests that the blood brain bar ier (BBB) prevents certain drugs and neurotoxins from gaining access to dopamine (DA) neurons in patients with Parkinson's disease (PD) unless a specific transport mech nism exists. However, we showed in animal, in vitro, and autopsy studies that the BB is dysfunctional in models of PD and patients. Animal and in vitro studies suggest d that products of activated microglial were responsible for this dysfunction. Ifbarri r function is compromised, the brain will be exposed to elements in the peripheral vasc lature. We hypothesize that BBB dysfunction williead to increased exposure 0 brain parenchyma to DA neurotoxins in the blood as well as peripheral immune syste mediators (T cells and monocytes) that will contribute to disease progression. Aim l' "II evaluate progressive DA neuron loss in mice with pre-existing DA lesions (induced b MPTP and LPS) for evidence of an increased entry of a tritium labeled, systemic By administered, DA neurotoxin (MPP+), and immune mediators. Aim 2 will assess fra tions from activated microglia (cell line and microglia isolated from DA lesioned mic for effects on endothelial cell (EC) monolayers (human cell line and mouse prim ry cultures) and changes in transport of DA toxins as well as transmigration of immu e mediators. These studies will also identify protein as well as ultrastructural cha ges (EM studies) in the tight junctions that create the BBB. We anticipate these stud es demonstrating that neuroinflammatory-mediated events affect p tein structure in tight junctions disrupting the BBB that leads to entry of peri heral vascular elements that contribute to further DA neuron loss and disease progressi n. These findings will systemat ically demonstrate, for the first time, that barrier d sfunction occurs in animal models of PD and identify potential mechanisms for this dy function. These findings would provide an entirely new hypothesis for progression pa hogenesis and identify new targets for therapeutic intervention in PD designed arou d affecting BBB integrity.