Mechanism of Microglial Recruitment in AD

Joseph El Khoury, MD
Massachusetts General Hospital (Charlestown, MA)
Year Awarded:
2004
Grant Duration:
April 1, 2004 to March 31, 2006
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2004110
Award Type:
Standard
Award Region:
US Northeastern

Mechanism of Microglial Recruitment in AD

Details


Data from humans with Alzheimer's disease and animal models of the disease indicate that the accumulation of microglia (inflammatory cells) in senile plaques contributes significantly to neural degeneration. Previous research from both Dr. El Khoury's laboratory and from other scientists indicates that beta-amyloid activates local microglia and astrocytes to produce chemokines, which then attract additional microglia to the plaque. The recruited microglia bind to the already deposited beta-amyloid and become activated to produce neurotoxins and other inflammatory mediators that cause neuronal damage. With prior support from ADR, Dr. El Khoury found that a small protein, called MCP-1, is necessary for the recruitment of microglia to sites of beta-amyloid deposition, and he has hypothesized that this protein may play a role in the recruitment of microglia to senile plaques in Alzheimer's disease. He is now working to build upon this data by investigating the specific mechanisms of recruitment, activation, and retention of microglia in senile plaques.

Publications

Medeiros LA, Khan T, El Khoury JB, Pham CL, Hatters DM, Howlett GJ, Lopez R, O'Brien KD, Moore KJ. Fibrillar amyloid protein present in atheroma activates CD36 signal transduction. J Biol Chem. 2004 Mar 12;279(11):10643-8. Epub 2003 Dec 29. PubMed  

. El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007 Apr;13(4):432-8. Epub 2007 Mar 11.  

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