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American Journal of Pathology, Vol 152, 307-317, Copyright © 1998 by American Society for Investigative Pathology
REGULAR ARTICLES |
SA Frautschy, F Yang, M Irrizarry, B Hyman, TC Saido, K Hsiao and GM Cole
Sepulveda Veterans Affairs Medical Center, GRECC, and Department of Medicine, University of California, Los Angeles 91343, USA.
Microglial activation is central to the inflammatory response in Alzheimer's Disease (AD). A recently described mouse line, Tg(HuAPP695.K670N/M671L)2576, expressing human amyloid precursor protein with a familial AD gene mutation, age-related amyloid deposits, and memory deficits, was found to develop a significant microglial response using Griffonia simplicifolia lectin or phosphotyrosine probe to identify microglia Both Griffonia simplicifolia lectin and phosphotyrosine staining showed increased numbers of intensely labeled, often enlarged microglia clustered in and around plaques, consistent with microglial activation related to beta-amyloid formation. Using quantitative image analysis of coronal phosphotyrosine-immunostained sections, transgene-positive 10- to 16-month-old, hemizygous, hybrid Tg2576 (APPsw) animals showed significantly increased microglial density and size in plaque-forming areas of hippocampus and frontal, entorhinal, and occipital cortex. Quantitative analysis of microglia as a function of distance from the center of plaques (double labeled for A beta peptide and microglia) revealed highly significant, two- to fivefold elevations in microglial number and area within plaques compared with neighboring regions. Tg2576 beta-amyloid-plaque-forming mice should be a useful system for assessing the consequences of the microglial-mediated inflammatory response to beta-amyloid and developing anti-inflammatory therapeutic strategies for Alzheimer's disease. These results provide the first quantitative link between beta- amyloid plaque formation and microglial activation in an animal model with neuritic plaques and memory deficits.
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D. W. Dickson Microglia in Alzheimer's Disease and Transgenic Models : How Close the Fit? Am. J. Pathol., June 1, 1999; 154(6): 1627 - 1631. [Full Text] [PDF]
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M. Stalder, A. Phinney, A. Probst, B. Sommer, M. Staufenbiel, and M. Jucker Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice Am. J. Pathol., June 1, 1999; 154(6): 1673 - 1684. [Abstract] [Full Text] [PDF]
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S. A. Frautschy, D. L. Horn, J. J. Sigel, M. E. Harris-White, J. J. Mendoza, F. Yang, T. C. Saido, and G. M. Cole Protease Inhibitor Coinfusion with Amyloid beta -Protein Results in Enhanced Deposition and Toxicity in Rat Brain J. Neurosci., October 15, 1998; 18(20): 8311 - 8321. [Abstract] [Full Text] [PDF]
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M. I. Brazil, H. Chung, and F. R. Maxfield Effects of Incorporation of Immunoglobulin G and Complement Component C1q on Uptake and Degradation of Alzheimer's Disease Amyloid Fibrils by Microglia J. Biol. Chem., May 26, 2000; 275(22): 16941 - 16947. [Abstract] [Full Text] [PDF]
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O. M. Mitrasinovic, G. V. Perez, F. Zhao, Y. L. Lee, C. Poon, and G. M. Murphy Jr. Overexpression of Macrophage Colony-stimulating Factor Receptor on Microglial Cells Induces an Inflammatory Response J. Biol. Chem., August 3, 2001; 276(32): 30142 - 30149. [Abstract] [Full Text] [PDF]
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