Spreading of Beta-Amyloid in Organotypic Mouse Brain Slices and Microglial Elimination and Effects on Cholinergic Neurons

The extracellular deposition of beta-amyloid (A beta) is one of the major characteristics in Alzheimer ' s disease (AD). The spreading hypothesis suggests that a pathological protein (similar to prions) spreads over the entire brain. The aim of the present study was to use organotypic brain slices of postnatal day 8-10 mice. Using collagen hydrogels, we applied different A beta peptides onto brain slices and analyzed spreading as well as glial reactions after eight weeks of incubation. Our data showed that from all tested A beta peptides, human A beta(42) had the most potent activity to spread over into adjacent target areas. This effect was potentiated when brain slices from transgenic AD mice (APP_SweDI) were cultured. When different brain areas were connected to the target slice the spreading activity was more intense, originating from ventral striatum and brain stem. Reactive glial-fibrillary acidic protein (GFAP) astrogliosis increased over time, but A beta depositions co-localized only with Iba1+ microglia but not with astrocytes. Application of human A beta(42) did not cause a degeneration of cholinergic neurons. We concluded that human A beta(42) spreads over into other target areas, causing activation of glial cells. Most of the spread A beta(42) was taken up by microglia, and thus toxic free A beta could not damage cholinergic neurons.

Automated summary

The study found that human Aβ(42) has the most potent spreading activity into adjacent target areas, activating glial cells. This effect was more pronounced in brain slices from transgenic AD mice, with connections from ventral striatum and brain stem intensifying the spreading activity of Aβ.