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、体外和尸检研究中显示，在帕金森病模型和患者中，BB功能障碍。动物和体外研究表明，激活的小胶质细胞产物是导致这种功能障碍的原因。如果屏障功能受损，大脑将暴露在周围血管中的元素中。我们假设BBB功能障碍会导致脑实质暴露于血液中DA神经毒素以及外周免疫系统介质(T细胞和单核细胞)的增加，这将有助于疾病的进展。目的L的“II”评估了预先存在DA损伤的小鼠的进行性DA神经元丢失，以寻找氚标记、全身注射、DA神经毒素(MPP+)和免疫介质进入增加的证据。目的研究小胶质细胞(DA损伤小鼠分离的细胞系和小胶质细胞)对内皮细胞(EC)单层(人细胞系和小鼠原代培养物)的作用，以及DA毒素转运和免疫介质迁移的变化。这些研究还将确定造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)。我们期待这些研究表明，神经炎性事件影响紧密连接中的蛋白质结构，破坏血脑屏障，导致周围血管元素进入，从而导致DA神经元的进一步丢失和疾病的进展。这些发现将首次系统地证明屏障D功能存在于PD动物模型中，并确定这种功能障碍的潜在机制。这些发现将为进展发病机制提供一个全新的假说，并为围绕影响血脑屏障完整性而设计的帕金森病的治疗干预确定新的靶点。

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.