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Title: | Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo | Authors: | Vasconcelos, Bruno STANCU, Ilie Cosmin Buist, Arjan Bird, Matthew Wang, Peng Van Kolen, Kristof Verheyen, An Kienlen-Campard, Pascal Octave, Jean-Noël Baatsen, Peter Moechars, Diederik DEWACHTER, Ilse Oosterhuyse, Alexandre |
Issue Date: | 2016 | Publisher: | SPRINGER | Source: | ACTA NEUROPATHOLOGICA, 131 (4) , p. 549 -569 | Abstract: | Genetic, clinical, histopathological and biomarker data strongly support Beta-amyloid (Aβ) induced spreading of Tau-pathology beyond entorhinal cortex (EC), as a crucial process in conversion from preclinical cognitively normal to Alzheimer's Disease (AD), while the underlying mechanism remains unclear. In vivo preclinical models have reproducibly recapitulated Aβ-induced Tau-pathology. Tau pathology was thereby also induced by aggregated Aβ, in functionally connected brain areas, reminiscent of a prion-like seeding process. In this work we demonstrate, that pre-aggregated Aβ can directly induce Tau fibrillization by cross-seeding, in a cell-free assay, comparable to that demonstrated before for alpha-synuclein and Tau. We furthermore demonstrate, in a well-characterized cellular Tau-aggregation assay that Aβ-seeds cross-seeded Tau-pathology and strongly catalyzed pre-existing Tau-aggregation, reminiscent of the pathogenetic process in AD. Finally, we demonstrate that heterotypic seeded Tau by pre-aggregated Aβ provides efficient seeds for induction and propagation of Tau-pathology in vivo. Prion-like, heterotypic seeding of Tau fibrillization by Aβ, providing potent seeds for propagating Tau pathology in vivo, as demonstrated here, provides a compelling molecular mechanism for Aβ-induced propagation of Tau-pathology, beyond regions with pre-existing Tau-pathology (entorhinal cortex/locus coeruleus). Cross-seeding along functional connections could thereby resolve the initial spatial dissociation between amyloid- and Tau-pathology, and preferential propagation of Tau-pathology in regions with pre-existing 'silent' Tau-pathology, by conversion of a 'silent' Tau pathology to a 'spreading' Tau-pathology, observed in AD. | Keywords: | Alzheimer’s disease;Amyloid beta;Heterotypic seeding;Prion-like;Tau;Amyloid beta-Peptides;Analysis of Variance;Animals;Disease Models, Animal;Green Fluorescent Proteins;HEK293 Cells;Humans;Immunohistochemistry;Mice, Transgenic;Mutation;Presenilin-1;Prion Proteins;Protein Aggregation, Pathological;Tauopathies;Transfection;tau Proteins | Document URI: | http://hdl.handle.net/1942/30333 | ISSN: | 0001-6322 | e-ISSN: | 1432-0533 | DOI: | 10.1007/s00401-015-1525-x | ISI #: | 000372297500005 | Rights: | The Author(s) 2016. This article is published with open access at Springerlink.com | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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Vasconcelos2016_Article_HeterotypicSeedingOfTauFibrill.pdf | Published version | 12.14 MB | Adobe PDF | View/Open |
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