title: Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo.
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.
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vasconcelos
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Ilie-Cosmin
authors.initials: IC
authors.lastname: Stancu
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, 2340, Beerse, Belgium.
authors.forename: Arjan
authors.initials: A
authors.lastname: Buist
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bird
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vanoosthuyse
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, 2340, Beerse, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Kolen
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, 2340, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Verheyen
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: Kienlen-Campard
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Octave
authors.affiliation: VIB11 vzw Center for the Biology of Disease, KU Leuven, 3000, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Baatsen
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, 2340, Beerse, Belgium.
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium. ilse.dewachter@uclouvain.be.
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D000072002:Prion Proteins / Q000378:metabolism* / Q000648:ultrastructure; D066263:Protein Aggregation, Pathological / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D000072002:Prion Proteins; D016875:tau Proteins; D049452:Green Fluorescent Proteins
keywords: Alzheimer’s disease; Amyloid beta; Heterotypic seeding; Prion-like; Tau