Microglial interactions with amyloid beta peptide

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The objectives of this proposal are to characterize the consequences of the interaction of the Abeta peptide with human microglia. In the brains of individuals affected by AD, microglia are clustered around the Abeta plaques. A range of experimental data have shown that microglia become activated to a pro-inflammatory state as a result of an interaction with Abeta. These activated microglia are producing a range of toxic products that can be causing damage to the neurons. There are still many mechanisms involved in the interaction of microglia with Abeta that remain to be worked out. We have developed a unique model, employing microglia cells that are derived from postmortem human brains, to study these mechanisms. The first specific aim of this application will compare the activation properties of different types of Abeta peptides on microglia in terms of their induction of macrophage colony stimulating factor, monocyte chemotactic protein, neurotoxic factor, superoxide radicals and expression of the enzyme myeloperoxidase. We will also examine whether antibody coated Abeta peptides have the same effect on microglial activation, and determine the relative roles of potential Abeta receptors in mediating this activation. In specific aim 2, we will characterize the expression of the urokinase plasminogen activator receptor (uPAR) by microglia. This receptor plays a central role in coordinating the migration and adhesion of inflammatory cells and treatment of microglia with Abeta increases the expression of uPAR. In conjunction with this, we will determine whether the ligand urokinase plasminogen activator is induced and regulated in the same manner as the receptor. The consequences of binding to microglial uPAR will be investigated to characterize which signaling pathways are activated. In specific aim 3, we will use immunochemical and biochemical techniques to study what is happening to the Abeta peptide once it has interacted with microglia. Microglia appear to have only limited abilities to degrade the Abeta peptides over time once phagocytosed. We propose to study whether the peptide is degraded, is complexed or undergoes other modifications. With the availability of gene array and isolation techniques and human genetic data, in specific aim 4 we propose to discover new consequences of Abeta-microglial interactions. Overall, the findings from the proposed research could extend our knowledge of the inflammatory events occurring in the AD brain.