Toll-Like Receptor Signaling in Alzheimer's Disease

Massachusetts General Hospital, Boston MA

Investigators

Linked publications, trials & patents

Abstract

Microglia are the principal innate immune cells of the brain. In Alzheimer's disease (AD) these cells bind B-amyloid (AB) and accumulate at sites of AB deposition, including senile plaques. Microglial interactions with AB promote a chronic inflammatory response characterized by the production of pro-inflammatory cytokines and chemokines, reactive oxygen and nitrogen species, and complement proteins. This sterile inflammation is maintained by persistent microglial activation by AB and leads to neuronal degeneration and increased AB deposition and therefore promotes disease progression. The receptors that bind AB and the signaling pathways triggered by AB that promote chronic inflammation are not fully understood. Our long-term goals are to identify the molecular mechanisms of microglial activation by AB and the impact of these pathways on AD pathogenesis. We hypothesize that Toll-like receptors (TLR), an evolutionarily ancient family of pattern recognition receptors that detect microbial ligands, initiate and maintain the microglial inflammatory response to AB . This hypothesis is based on preliminary findings that targeted deletion of the TLR signaling adaptor MyD88 abrogates microglial inflammatory responses to AB in vitro and in vivo. In this proposal, we will define the TLRs and co-receptors responsible for initiating this signaling, their impact on microglial inflammatory responses and the implications for disease. Specifically, we will (1) Define the role of TLR ligation and signaling on microglial responses to AB in vitro, (2) Determine the role of AB co-receptors in facilitating TLR signaling, and (3) Determine the impact of AB -TLR signaling on Alzheimer's disease pathology in vivo. Understanding the mechanism(s) of microglial interactions with AB 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 to promote microglial clearance of AB while downregulating their neurotoxic effects.