INFLAMMATORY MECHANISMS IN ALZHEIMER'S DISEASE: MICROGLIAL SIGNALING AND TRANSCRIPTIONAL REGULATION





G. Landreth, C. Combs, C. Karlo and S. Sundararajan

Alzheimer Research Lab, Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106



The pathogenesis of Alzheimer?s Disease (AD) involves inflammatory processes as evidenced by the presence of abundant reactive microglia associated with the senile plaque and elevated levels of their proinflammatory secretory products in the brain. Exposure of microglia or monocytes to fibrillar forms of Aß results in the activation of tyrosine kinase-based signaling cascades resulting in a broad range of proinflammatory responses. The amyloid fibrils interact with a cell surface receptor complex comprised of the B-class scavenger receptor CD36, the a6b1 integrin and the integrin associated protein CD47. The assembly of this receptor complex leads to its physical linkage to intracellular signaling molecules and activation of downstream signaling cascades. Non-steroidal anti-inflammatory drug treatment (NSAID) has been shown to inhibit microglial activation, dramatically reduce risk for AD and delay disease progression. An unappreciated target of NSAIDs action is the transcription factor, peroxisome proliferator activated receptor gamma (PPARg), whose transcriptional actions are activated upon binding of NSAIDs, its natural lipid ligands and drugs of the thiazolidinedione class. PPARg activation directly inhibits amyloid-stimulated proinflammatory gene transcription and microglial activation. We argue that the efficacy of NSAIDs in the treatment of AD may be a consequence of their actions on PPARg rather than on their canonical targets, the cyclooxygenases. The ability of these agents to inhibit a broad range of inflammatory responses suggests that PPARg agonists, and particularly newly developed drugs of the thiazolidinedione class, may be of utility in AD and other CNS indications with an inflammatory component.




Key words: Alzheimer's disease, inflammation, amyloid, signal transduction







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