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Funded Studies

Activation of Receptor for Advanced Glycation Endproducts (RAGE) on Microglia: A Novel Inflammatory Mechanism Contributing to PD Pathogenesis

There is now considerable and growing evidence that Parkinson's disease (PD) is associated with inflammation in the brain. Several small soluble proteins that are commonly secreted during inflammatory responses have been found elevated in cerebrospinal fluid or brains of Parkinson's patients. This has suggested that inflammatory responses contribute to the disease. But, it remains unclear whether inflammation is secondary to the changes taking place in the disease-affected neurons, such as neurons that produce dopamine and are localized in the substantia nigra (the region primarily affected by PD). These neurons accumulate neuromelanin, which is dopamine that has become oxidized and polymerized during aging. Microglia, the major inflammatory cells in the brain, have been shown to contain neuron-derived neuromelanin presumably by a process called phagocytosis, which enables the internalization of big molecules. These neuromelanin-containing microglia display characteristics of being activated. Activated microglia can secrete inflammatory mediators and molecules that are toxic to neurons. This led us to hypothesize that neuromelanin or oxidized dopamine may induce changes in microglial properties and functions in PD. Chronic exposure of microglia to oxidized dopamine could provide a self-amplifying injurious process that might accelerate the disease. Our preliminary data not only supported this theory, but also revealed that a specific receptor expressed by microglia mediated this process. This receptor (receptor for advanced glycation endproducts, abbreviated as RAGE) has previously been shown to be involved in diabetes, atherosclerosis, and Alzheimer's disease. We propose to study how oxidized dopamine, through this receptor, contributes to the inflammation in PD and whether blocking the interaction between RAGE and oxidized dopamine could be one means to reduce the adverse effects of inflammatory responses in PD.


Researchers

  • Lih-Fen Lue, PhD

    Sun City, AZ United States


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