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.

Public Health Relevance

In Alzheimer's disease (AD), microglial interactions with ?-amyloid peptide promote chronic sterile inflammation that leads to neuronal degeneration, increased ?-amyloid deposition and disease progression. Understanding the mechanisms of microglial interactions with ?-amyloid and identifying the receptors involved in promoting inflammation will provide valuable insight into the role of these cells in the pathogenesis of AD and possibly allow the use of microglia as therapeutic targets for AD by promoting their ability to clear ?-amyloid while downregulating their harmful and neurotoxic effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG032349-05S2
Application #
8679097
Study Section
Program Officer
Petanceska, Suzana
Project Start
2013-09-13
Project End
2015-09-12
Budget Start
2013-09-13
Budget End
2015-09-12
Support Year
5
Fiscal Year
2013
Total Cost
$164,839
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Gold, Maike; El Khoury, Joseph (2015) ?-amyloid, microglia, and the inflammasome in Alzheimer's disease. Semin Immunopathol 37:607-11
Hickman, Suzanne E; El Khoury, Joseph (2014) TREM2 and the neuroimmunology of Alzheimer's disease. Biochem Pharmacol 88:495-8
Sheedy, Frederick J; Grebe, Alena; Rayner, Katey J et al. (2013) CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 14:812-20
Hickman, Suzanne E; Kingery, Nathan D; Ohsumi, Toshiro K et al. (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16:1896-905
Frenkel, Dan; Wilkinson, Kim; Zhao, Lingzhi et al. (2013) Scara1 deficiency impairs clearance of soluble amyloid-? by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. Nat Commun 4:2030
Hickman, Suzanne E; El Khoury, Joseph (2013) The neuroimmune system in Alzheimer's disease: the glass is half full. J Alzheimers Dis 33 Suppl 1:S295-302
Wilkinson, Kim; El Khoury, Joseph (2012) Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer's disease. Int J Alzheimers Dis 2012:489456
Glicksman, Marcie A (2011) The preclinical discovery of amyotrophic lateral sclerosis drugs. Expert Opin Drug Discov 6:1127-38
Wilkinson, Kim; Boyd, Justin D; Glicksman, Marcie et al. (2011) A high content drug screen identifies ursolic acid as an inhibitor of amyloid beta protein interactions with its receptor CD36. J Biol Chem 286:34914-22
Stewart, Cameron R; Stuart, Lynda M; Wilkinson, Kim et al. (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11:155-61

Showing the most recent 10 out of 12 publications