Mechanism of Microglial Recruitment in Alzheimer's Disease

Joseph El Khoury, MD
Massachusetts General Hospital (Charlestown, MA)
Year Awarded:
2002
Grant Duration:
April 1, 2002 to March 31, 2004
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2002217
Award Type:
Standard
Award Region:
US Northeastern

Mechanism of Microglial Recruitment in Alzheimer's Disease

Details


The senile plaque, composed of aggregations of beta amyloid protein, is a pathological hallmark of Alzheimer's disease. Accumulation of beta amyloid in the brain leads to the activation of microglia cells. Microglia cells are inflammatory cells that can produce substances that are toxic to neurons and lead to neuronal degeneration. Studies have shown that there are key steps for neuronal damage from the accumulation of microglia in senile plaques. First, the binding of microglia to beta amyloid occurs. Second, microglia are induced to produce chemoattractants that recruit additional microglia to the beta amyloid deposit. Finally, the production of neurotoxins from the recruited microglia cause cellular damage. Dr. El Khoury is studying the mechanisms of the recruitment of microglia to senile plaques in AD using an in vitro cellular model for microglia interactions, post-mortem human brain tissue from AD patients and transgenic mice. He plans to identify chemoattractants produced by microglia and the receptors that are involved, the expression of the chemoattractants and their receptors in brain tissue and in mouse models of AD, and the effects of disrupting the expression of chemoattractants and the receptors in the recruitment of microglia. Understanding the mechanisms of recruitment of microglia to plaques and how they become activated to produce neurotoxins may help to identify new targets for the development of treatments for AD.

Publications

Moore, K.J., El Khoury, J., Medeiros, L.A., Terada, K., Geula, C., Luster, A.D.,And Freeman, M.W. (2002) A CD36 initiated signaling cascade mediates inflammatory effects of beta-amyloid. J Biol. Chem. 277(49):47373-47379.  

El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, Freeman MW, Luster AD (2003) CD36 mediates the innate host response to beta-amyloid. J Exp Med. 2003 Jun 16;197(12):1657-66. Epub 2003 Jun 9.  

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