Blood Brain Barrier Dysfunction in Parkinson's Diseases

传统认为，血脑屏障（BBB）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，除非存在特定的转运机制。然而，我们在动物、体外和尸检研究中发现，BB在PD模型和患者中功能障碍。动物和体外研究表明，活化的小胶质细胞的产物是这种功能障碍的原因。如果巴里功能受损，大脑将暴露于周围血管系统中的元素。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），这将有助于疾病的进展。目的II评估具有预先存在的DA损伤（诱导的B MPTP和LPS）的小鼠中进行性DA神经元损失，以获得氚标记的全身性施用的DA神经毒素（MPP+）和免疫介质的进入增加的证据。目的2将评估活化的小胶质细胞（细胞系和从DA损伤小鼠分离的小胶质细胞）的组分对内皮细胞（EC）单层（人细胞系和小鼠内皮细胞培养物）的影响以及DA毒素转运和免疫介质迁移的变化。这些研究还将鉴定形成血脑屏障的紧密连接中的蛋白质和超微结构变化（EM研究）。我们预期这些研究表明，神经炎症介导的事件影响紧密连接中的蛋白质结构，破坏BBB，导致进一步DA神经元损失和疾病进展的血管成分进入。这些发现将首次系统地证明屏障功能障碍发生在PD动物模型中，并确定这种功能障碍的潜在机制。这些发现将为进展性疾病的发生提供一个全新的假设，并为PD的治疗干预确定新的靶点，这些治疗干预旨在影响BBB的完整性。

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.