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.

Public Health Relevance

Given our preliminary data and the anticipat d results from the two revised specific aims, we propose that blood brain barrier (B B) compromise occurs in the early stages of Parkinson's disease (PD). Compromised B B integrity leads to increased entry of peripheral toxins and/or peripheral cells (T c lis and monocytes) that are directed at dopamine (DA) neuron neoantigens formed a a result of neuroinflammation. The increased entry of peripheral toxins, and in p rticular immune cells directed at the DA neuron, creates a feed-forward, se]f-sustainin neurodegenerative process that contributes to further DA neuron loss and th s the progressive neurodegeneration of DA neurons that characterizes PD. Since our prel minary data also suggests that this selfsllstaining process contributes to DA neuron loss, using rugs that prevent further barrier compromise (Le., avp3 integrin antago ists or drugs that increase adenylate cyclase activity in endothelial cells) should slo progression. Since drugs that perform these functions (e.g., cilengitide or P adrenerg c agonists and caffeine, respectively) are already available and approved for patient use demonstrating the effectiveness of these drugs in animal models would facilitate clinic 1 trials for their effectiveness in slowing PD progression. These drugs would theoretica ly be most effective in the early stages of disease meaning that their ability to slow dise se progression would have a significant impact on the quality of life of PD patients, re uce health care costs and allow many patients to continue to work.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Sieber, Beth-Anne
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Rush University Medical Center
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