Abstract
The extracellular deposition of β-amyloid (Aβ) 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 Aβ peptides onto brain slices and analyzed spreading as well as glial reactions after eight weeks of incubation. Our data showed that from all tested Aβ peptides, human Aβ42 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 Aβ depositions co-localized only with Iba1+ microglia but not with astrocytes. Application of human Aβ42 did not cause a degeneration of cholinergic neurons. We concluded that human Aβ42 spreads over into other “target areas”, causing activation of glial cells. Most of the spread Aβ42 was taken up by microglia, and thus toxic free Aβ could not damage cholinergic neurons.
Highlights
The life expectancy of humans has markedly increased over the last 100 years
We demonstrated that human Aβ42 applied to the donor slice via a collagen hydrogel spreads from the donor slice over to the adjacent target slice
This spreading is accompanied by microglial activation and elimination of toxic hAβ42, which prevents cholinergic cell death
Summary
The life expectancy of humans has markedly increased over the last 100 years. As age is the main risk factor for Alzheimer’s disease (AD), the number of patients suffering from AD and mixed forms of dementia will dramatically increase over the 50 years.It is expected that there will be about 80 million AD patients worldwide in 2050. The life expectancy of humans has markedly increased over the last 100 years. The causes of AD are yet unknown but at present the Aβ cascade, which is the most prominent hypothesis [2], is surrounded by more and more controversy [3,4]. It is not entirely clear when and how the AD pathology starts, but there is growing evidence that spreading of toxic, low molecular weight Aβ oligomers plays a central role [5,6]
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