Innate immune signaling in Alzheimer's disease pathogenesis
This award seeks to study the role of the innate immune system in AD pathogenesis. and the role of Toll-like receptors in mediating the microglial inflammatory response. Microglia likely play a key role in the clearance of Aß as well as in more chronic inflammatory changes as a result of Aß activation.
Microglia are the primary immune cells of the brain and in Alzheimer's disease (AD) these cells accumulate at sites of ß-amyloid (Aß) deposits, including senile plaques. Microglial interactions with Aß incite a chronic inflammatory response that leads to neuronal degeneration, increased Aß deposition and disease progression. The microglial receptors and signaling pathways triggered by Aß that promote this chronic inflammation remain a matter of speculation. Our long-term goals are to identify the mechanisms of microglial activation by Aß and the impact of these pathways on disease. We hypothesize that the Toll-like receptors (TLR), an evolutionarily ancient family of microbial recognition receptors, initiate and maintain the microglial inflammatory response to Aß. This hypothesis is based on preliminary findings that targeting of members of this signaling pathway block microglial inflammatory responses to Aß. We propose to define the TLRs and co-receptors responsible for initiating this signaling, their impact on microglial inflammatory responses and the implications for disease. Understanding the mechanism(s) of microglial interactions with Aß and identifying the receptors involved in these interactions will provide valuable insight into the role of these cells in the pathogenesis of AD and potentially identify therapeutic targets in AD.