Role of the innate immune response in the development of Alzheimer's disease

Kathryn Moore, PhD
New York University (New York, NY)
Year Awarded:
Grant Duration:
April 1, 2008 to March 31, 2011
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Northeastern
Kathryn Moore, PhD

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 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.


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.

Research Updates

Dr. Kathryn Moore and colleagues identified a trigger mechanism common to both atherosclerosis and Alzheimer's disease that involves the activation of the innate immune response. The innate immune response provides an immediate, but not long-lasting, defense against infection. Three cell surface proteins, called TLR4, TLR6 and CD36, normally recognize specific protein patterns found on microbes to activate the immune system to destroy the foreign invaders.  In this research grant, Dr. Moore discovered that these three proteins can also assemble into a newly-identified complex that recognizes both Alzheimer's-associated beta-amyloid and the atherosclerosis-associated protein oxidized LDL. This interaction further induces inflammation signals that may promote the development of these two diseases. Dr. Moore has identified a common pathway involved in triggering and maintaining inflammation in atherosclerosis and Alzheimer's disease. These findings present exciting opportunities to treat both of these aging diseases by creating new therapies targeting TLR4, TLR6 and CD36.


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.)

Don't miss out.
Receive research updates, inspiring stories, and expert advice
Please enter your first name.
Please enter your last name.
Keep me informed about: *
Please select at least one.
You must select at least one disease category.