STRATEGIES FOR INHIBITING THE Aβ-STIMULATED MICROGLIAL SIGNALING RESPONSE IN ALZHEIMER’S DISEASE

Colin K. Combs

Department of Biomedical Sciences, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58202-9037, USA

Abstract

Accumulation of amyloid-β (Aβ) peptide containing plaques and associated microgliosis are hallmarks of Alzheimer's disease (AD) brains. Aβ peptide is hypothesized to act as a stimulus for microglia leading to activation of non-receptor tyrosine kinases, subsequent transcriptional changes, and acquisition of a proinflammatory phenotype. Therefore, the signaling pathways mediating Aβ-stimulated microglial activation represent attractive therapeutic targets for anti-inflammatory therapies. We have observed that members of the Src family of kinases are activated by Aβ stimulation followed by subsequent transcriptional activation of nuclear factor of activated T cells (NFAT). Based upon these findings, we identified a small molecule with dose dependent selectivity for inhibiting the Aβ-stimulated microglial increase in active, phosphorylated levels of Lyn and Src kinases compared to MAP kinases as well as the subsequent increase in TNFα and IL-6 secretion. In addition to tyrosine kinase activation, we observed that Aβ stimulated a subsequent isoform selective increase in microglial NFATc2 activity. Deletion of NFATc2 or treatment of microglia with the calcineurin/NFAT inhibitor, FK506, was sufficient to attenuate Aβ-stimulated microgliosis in vitro or in vivo using a well-known AD mouse model, APP/PS1 mice. Based upon these findings, the Aβ-stimulated microglial signaling response can be targeted with novel small molecule strategies to ameliorate the proinflammatory component of AD pathophysiology.