We found a match
Your institution may have rights to this item. Sign in to continue.
- 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; Vanoosthuyse, Alexandre; Kolen, Kristof; Verheyen, An; Kienlen-Campard, Pascal; Octave, Jean-Noël; Baatsen, Peter; Moechars, Diederik; Dewachter, Ilse
- 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.
- Subjects
AMYLOID beta-protein; ALZHEIMER'S disease; HISTOPATHOLOGY; BRAIN; PRIONS
- Publication
Acta Neuropathologica, 2016, Vol 131, Issue 4, p549
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-015-1525-x