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J Neurosci. 2016 May 4;36(18):5084-93. doi: 10.1523/JNEUROSCI.0258-16.2016.

Conversion of Synthetic Aβ to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model.

Author information

1
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen D-72076, Germany, DZNE, German Center for Neurodegenerative Diseases, Tübingen D-72076, Germany, Graduate School for Cellular and Molecular Neuroscience, University of Tübingen, Tübingen D-72076, Germany.
2
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen D-72076, Germany, DZNE, German Center for Neurodegenerative Diseases, Tübingen D-72076, Germany.
3
Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, Frankfurt/Main D-60590, Germany.
4
Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg D-79104, Germany, and.
5
Department of Chemistry, IFM, Linköping University, Linköping SE-581 83, Sweden.
6
Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg D-79104, Germany, and bernd.heimrich@zfn.uni-freiburg.de mathias.jucker@uni-tuebingen.de.
7
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen D-72076, Germany, DZNE, German Center for Neurodegenerative Diseases, Tübingen D-72076, Germany, bernd.heimrich@zfn.uni-freiburg.de mathias.jucker@uni-tuebingen.de.

Abstract

The aggregation of amyloid-β peptide (Aβ) in brain is an early event and hallmark of Alzheimer's disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral β-amyloidosis by establishing a long-term hippocampal slice culture (HSC) model. While no Aβ deposition was noted in untreated HSCs of postnatal Aβ precursor protein transgenic (APP tg) mice, Aβ deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic Aβ. Seeded Aβ deposition was also observed under the same conditions in HSCs derived from wild-type or App-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic Aβ species determined the conformational characteristics of HSC Aβ deposition. HSC Aβ deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic Aβ, homogenates of Aβ deposits containing HSCs induced cerebral β-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic Aβ into a potent in vivo seeding-active form.

SIGNIFICANCE STATEMENT:

In this study, we report the seeded induction of Aβ aggregation and deposition in long-term hippocampal slice cultures. Remarkably, we find that the biological activities of the largely synthetic Aβ aggregates in the culture are very similar to those observed in vivo This observation is the first to show that potent in vivo seeding-active Aβ aggregates can be obtained by seeded conversion of synthetic Aβ in a living (wild-type) cellular environment.

KEYWORDS:

alzheimer; amyloid; neurodegeneration; prion-like seeding; slice culture

PMID:
27147660
PMCID:
PMC6601857
DOI:
10.1523/JNEUROSCI.0258-16.2016
[Indexed for MEDLINE]
Free PMC Article

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