Heterotypic Seeding of Tau Fibrillization by Pre-Aggregated Abeta Provides Potent Seeds for Prion-Like Seeding and Propagation of Tau-pathology in Vivo

Acta Neuropathol. 2016 Apr;131(4):549-69. doi: 10.1007/s00401-015-1525-x. Epub 2016 Jan 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / toxicity
  • Analysis of Variance
  • Animals
  • Disease Models, Animal
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Mice, Transgenic
  • Mutation / genetics
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Prion Proteins / metabolism*
  • Prion Proteins / ultrastructure
  • Protein Aggregation, Pathological / chemically induced
  • Protein Aggregation, Pathological / metabolism*
  • Protein Aggregation, Pathological / pathology
  • Tauopathies / genetics
  • Tauopathies / metabolism*
  • Transfection
  • tau Proteins / genetics
  • tau Proteins / metabolism*
  • tau Proteins / ultrastructure

Substances

  • Amyloid beta-Peptides
  • PSEN1 protein, human
  • Presenilin-1
  • Prion Proteins
  • tau Proteins
  • Green Fluorescent Proteins