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Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus
Published on: June 17, 2015
Spreading of Beta-Amyloid in Organotypic Mouse Brain Slices and Microglial Elimination and Effects on Cholinergic
Kurt Moelgg1, Faryal Jummun1, Christian Humpel1
1Laboratory of Psychiatry and Experimental Alzheimer's Research, Department Psychiatry I, Medical University of Innsbruck, Anichstr 35, A-6020 Innsbruck, Austria.
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.
Insights
Human beta-amyloid (Aβ) peptides spread through brain tissue, activating glial cells. Microglia uptake most Aβ, protecting cholinergic neurons from damage in Alzheimer's disease models.
Area of Science:
- Neuroscience
- Pathology
- Molecular Biology
Background:
- Extracellular deposition of beta-amyloid (Aβ) is a hallmark of Alzheimer's disease (AD).
- The 'spreading hypothesis' posits that pathological proteins propagate throughout the brain, similar to prions.
Purpose of the Study:
- To investigate the spreading potential of different Aβ peptides in organotypic mouse brain slices.
- To analyze glial cell reactions to Aβ deposition over an eight-week incubation period.
Main Methods:
- Organotypic brain slices from postnatal day 8-10 mice were cultured.
- Collagen hydrogels were used to apply various Aβ peptides to the slices.
- Spreading patterns and glial responses (GFAP, Iba1) were analyzed after eight weeks.
Main Results:
- Human Aβ42 demonstrated the most potent spreading activity into adjacent areas.
- Spreading was enhanced in slices from transgenic AD mice (APP_SweDI).
- Ventral striatum and brain stem showed intense Aβ spreading activity when connected to target slices.
- Aβ depositions co-localized with Iba1+ microglia but not astrocytes; GFAP astrogliosis increased over time.
- Human Aβ42 application did not lead to cholinergic neuron degeneration.
Conclusions:
- Human Aβ42 effectively spreads to other brain areas, triggering glial cell activation.
- Microglia play a significant role in clearing spread Aβ42, potentially preventing cholinergic neuron damage.
