Conversion of Synthetic A beta to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model
2016 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 18, 5084-5093 p.Article in journal (Refereed) PublishedText
The aggregation of amyloid-beta peptide (A beta) inbrain is an early event and hallmark of Alzheimers disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral beta-amyloidosis by establishing a long-term hippocampal slice culture(HSC) model. While no A beta deposition was noted in untreated HSCs of postnatal A beta precursor protein transgenic (APP tg) mice, A beta 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 A beta. Seeded A beta 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 A beta species determined the conformational characteristics of HSCA beta deposition. HSCA beta deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic A beta, homogenates of A beta deposits containing HSCs induced cerebral beta-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic A beta into a potent in vivo seeding-active form.
Place, publisher, year, edition, pages
SOC NEUROSCIENCE , 2016. Vol. 36, no 18, 5084-5093 p.
alzheimer; amyloid; neurodegeneration; prion-like seeding; slice culture
IdentifiersURN: urn:nbn:se:liu:diva-130301DOI: 10.1523/JNEUROSCI.0258-16.2016ISI: 000378276600016PubMedID: 27147660OAI: oai:DiVA.org:liu-130301DiVA: diva2:950498
Funding Agencies|German Federal Ministry of Education and Research Grant [BMBF-ALZKULT 031A198]; EU Joint Programme on Neurodegenerative Diseases Grant JPND-NeuTARGETs; German Research Foundation [DFG DE 551/11-2, VL 72/1-2]2016-07-312016-07-282016-07-31