Alzheimer's Disease Research - Current Award

	Kathryn Moore, Ph.D. New York University New York, NY Title: Innate immune signaling in Alzheimer's disease pathogenesis Non-Technical Title: Role of the innate immune response in the development of Alzheimer's disease Duration: April 1, 2008 - March 31, 2011 Award Type: Standard Award Amount: $265,000
Summary: This award seeks to study the role of the innate immune system in AD pathogenesis. and the role of Toll-like recceptors 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.

Details:

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 signalling, 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.

Publications:

Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, El Khoury J, Golenbock DT, Moore KJ. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunology. 2010; 11(2):155-61.  

(This study identifies an innate immune signaling complex composed of CD36 and a novel Toll-like receptor (TLR) heterodimer of TLR4 and TLR6 that mediates the inflammatory response to atherogenic LDL and -amyloid, including the neurotoxicity that is pathogenomonic of Alzheimer's disease. This work identifies a common molecular mechanism underlying innate immune activation in atherosclerosis and Alzheimer disease. This was featured in a press release from Nature Immunology and highlighted in Nature Reviews in Immunology.)

Progress Updates:

Our work demonstrates that three cell surface proteins, called TLR4, TLR6 and CD36, previously implicated in the recognition of specific body-invading microbes, also assemble to form a newly-identified protein complex that recognizes both the Alzheimer’s disease beta-amyloid peptide and the atherosclerosis-associated oxidized LDL. Once this new complex binds beta-amyloid or oxidized LDL, it induces pro-inflammatory mediators that are implicated in the pathology of Alzheimer's disease and atherosclerosis. These findings identify a common molecular pathway involved in triggering and maintaining inflammation in atherosclerosis and Alzheimer's disease and indicate an opportunity to devise therapies that may be effective in treating both of these conditions. We have recently published this work in the journal Nature Immunology and it was also highlighted in the prestigious scientific journal, Nature Reviews in Immunology.