Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-β plaque formation in organotypic hippocampal slice cultures

The role of microglia in amyloid-beta (A beta) deposition is controversial. In the present study, an organotypic hippocampal slice culture (OHSC) system with an in vivo-like microglial-neuronal environment was used to investigate the potential contribution of microglia to A beta plaque formation. We found that microglia ingested A beta, thereby preventing plaque formation in OHSCs. Conversely, A beta deposits formed rapidly in microglia-free wild-type slices. The capacity to prevent A beta plaque formation was absent in forebrain microglia from young adult but not juvenile 5xFamilial Alzheimer's disease (FAD) mice. Since no loss of A beta clearance capacity was observed in both wild-type and cerebellar microglia from 5xFAD animals, the high A beta(1-42) burden in the forebrain of 5xFAD animals likely underlies the exhaustion of microglial A beta clearance capacity. These data may therefore explain why A beta plaque formation has never been described in wild-type mice, and point to a beneficial role of microglia in AD pathology. We also describe a new method to study A beta plaque formation in a cell culture setting.