CARD9 attenuates Ab pathology and modifies microglial responses in an Alzheimer's disease mouse model
Although significant progress in recent years has been made in defining key innate immune receptors involved in Alzheimer's disease (AD), our knowledge of the specific intracellular signaling molecules that coordinate immune responses in AD remains poorly defined. In these studies, we have identified a previously undescribed role for the innate immune signaling molecule CARD9 in an amyloid beta (Ab)-mediated mouse model of AD. We specifically demonstrate that CARD9 deletion in the 5xFAD mouse model of AD leads to impaired control of Ab, worsened cognitive decline, and aberrant microglial activation. We further show that pharmacological activation of CARD9 provides a strategy to boost Ab clearance from the hippocampus. Collectively, these findings uncover a previously uncharacterized molecular signaling molecule used by the innate immune system in Ab-mediated neurological disease, and help to establish CARD9 as a novel molecular player that can be targeted in AD. Overall design: Comparison of 5xFAD microglial response with or without Card9 function. 4 replicates per group of non disease (WT), Card9-deficient, 5xFAD, and 5xFAD Card9 deficient