): Microglia are immune-system cells associated with senile plaques containing B-amyloid (AB) in Alzheimer's disease (AD). Although microglia are an integral part of senile plaques, their role in the development of A is not known. Because microglia are phagocytic cells, it has been suggested that microglia may function as plaque-attacking scavenger cells. It has also been suggested that microglia may participate in the development of Alzheimer's disease by initiating an inflammatory response. Microglia bind and internalize fibrillar microaggregates of AB that resemble those present in dense AD plaques. The internalized fibrillar AB is delivered to late endosomes and lysosomes, but it is only partially degraded. Undigested fibrillar AB is released over a period of several days. Soluble AB adsorbed to carrier proteins is also degraded poorly by microglia. In contrast to microglia, cultured macrophages can degrade fibrillar AB rapidly and completely. We will compare the two cell types to determine why macrophages are more effective at degradation of AB, and we will use this information to boost the degradative capability of microglia in culture. We will test the hypothesis that microglia can participate in the accumulation of amyloid plaques by impaired degradation, by promotion of plaque formation in acidic endosomes, by remodeling of plaque in endosomes and lysosomes, and by release of amyloid-like particles. We will study the interaction of plaque with microglia using digital fluorescence microscopy, confocal microscopy, electron microscopy, and biochemical analysis. We will analyze the mechanisms of degradation of AB amyloid in microglia and also determine whether soluble AB peptides become incorporated into insoluble AB in the endosomes and lysosomes of microglia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034761-06
Application #
6393757
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Murphy, Diane
Project Start
1995-09-30
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
6
Fiscal Year
2001
Total Cost
$254,250
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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