Microglial response to amyloid plaques in APPsw transgenic mice

Sally A. Frautschy, Fusheng Yang, Michael Irrizarry, Brad Hyman, T. C. Saido, Karen Hsiao, Greg M. Cole

Research output: Contribution to journalArticlepeer-review

462 Scopus citations

Abstract

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 β-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 Aβ peptide and microglia) revealed highly significant, two- to fivefold elevations in microglial number and area within plaques compared with neighboring regions. Tg2576 β-amyloid-plaque-forming mice should be a useful system for assessing the consequences of the microglial-mediated inflammatory response to β-amyloid and developing anti-inflammatory therapeutic strategies for Alzheimer's disease. These results provide the first quantitative link between β-amyloid plaque formation and microglial activation in an animal model with neuritic plaques and memory deficits.

Original languageEnglish (US)
Pages (from-to)307-317
Number of pages11
JournalAmerican Journal of Pathology
Volume152
Issue number1
StatePublished - Jan 1998

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