MICROGLIAL RESPONSE TO AMYLOID PLAQUES IN APPSW TRANSGENIC MICE

Microglial activation is central to the inflammatory response in Alzhe imer's Disease (AD). A recently de scribed mouse line, Tg(HuAPP695.K67 0N/M671L)2576, expressing human amyloid precursor protein with a famil ial AD gene mutation, age-related amyloid deposits, and memory deficit s, was found to develop a significant microglial response using Griffo nia simplicifolia lectin or phosphotyrosine probe to identify microgli a, Both Griffonia simplicifolia lectin and phosphotyrosine staining sh owed 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, Qu antitative analysis of microglia as a function of distance from the ce nter of plaques (double labeled for A beta peptide and microglia) reve aled highly significant, two-to fivefold elevations in microglial numb er and area within plaques compared with neighboring regions, Tg2576 b eta-amyloid-plaque-forming mice should be a useful system for assessin g 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 i n an animal model with neuritic plaques and memory deficits.