P2‐376: Therapeutic treatment of AICAR for microglial inflammation in Alzheimer's disease

Background: Pro-inflammatory cytokines have been detected in brains of individuals with Alzheimer’s disease (AD) andmay play a significant role in the pathogenesis of AD. Our earlier reports investigated glial cell responses to LPS and A b, by upregulating the expression of cytokines TNFa, IL-1 b, and IL-6, as well as iNOS and COX-2. The present study was undertaken to investigate the therapeutic benefits of AICAR (a potent activator of AMP-activated protein kinase) in blocking the pro-oxidant/proinflammatory responses inmicroglia. Objectives: Ourmain objectives were a) to understand the activation aswell release of cytokines from activatedmicroglia in response to accumulated A b, and possible therapeutic benefits of AICAR. Methods: BV-2 microglia were used in these studies to understand LPS/ SMase/A b stimulated signaling mechanisms of NF k B pathway leading to the release of NO, ROS generation , release of inflammatory cytokine (TNFa, IL-1 b, IL-6) as well the scavenging macrophage like phagocytic functions of microglia.Results:AICAR inhibits LPS, and Smase activated cytokine release and NO production. AICAR also does promote A b phagocytosis. Further we observed a reduction in the stress signalingwith a significant lowering in p-ERK, p-p38, p-Akt (ser 473) as well as significant reduction of proteins such as p-NIK, p-IKK a/b and in p-p65 translocation. Conclusions: Microglia play an active role in triggering the immune cytokine responses in the neuro-inflammatory process ofAD. AICAR treatment effectively blocked cytokine release, A b phagocytosis by regulating NF k B pathways and perhaps is effective for therapeutics of AD.