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

Biomolecules (2021-04-04)
Kurt Moelgg, Faryal Jummun, Christian Humpel
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The extracellular deposition of ฮฒ-amyloid (Aฮฒ) is one of the major characteristics in Alzheimerยดs 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 Aฮฒ peptides onto brain slices and analyzed spreading as well as glial reactions after eight weeks of incubation. Our data showed that from all tested Aฮฒ peptides, human Aฮฒ42 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 Aฮฒ depositions co-localized only with Iba1+ microglia but not with astrocytes. Application of human Aฮฒ42 did not cause a degeneration of cholinergic neurons. We concluded that human Aฮฒ42 spreads over into other "target areas", causing activation of glial cells. Most of the spread Aฮฒ42 was taken up by microglia, and thus toxic free Aฮฒ could not damage cholinergic neurons.

MATERIALS
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Sigma-Aldrich
Amyloid ฮฒ-Protein Fragment 25-35, โ‰ฅ97% (HPLC)
Sigma-Aldrich
Anti-Actin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-Choline Acetyltransferase Antibody, Chemiconยฎ, from goat
Sigma-Aldrich
Protease Inhibitor Cocktail, for use with mammalian cell and tissue extracts, DMSO solution
Sigma-Aldrich
Anti-Glial Fibrillary Acidic Protein Antibody, Chemiconยฎ, from chicken