Trans-seeding of Alzheimer-related tau protein by a yeast prion

Alzheimers Dement. 2022 Dec;18(12):2481-2492. doi: 10.1002/alz.12581. Epub 2022 Feb 9.

Abstract

Abnormal tau protein aggregates constitute a hallmark of Alzheimer's disease. The mechanisms underlying the initiation of tau aggregation in sporadic neurodegeneration remain unclear. Here we investigate whether a non-human prion can seed tau aggregation. Due to their structural similarity with tau aggregates, we chose Sup35NM yeast prion domain fibrils for explorative tau seedings. Upon in vitro incubation with tau monomers, Sup35NM fibrils promoted the formation of morphologically distinct tau fibril strains. In vivo, intrahippocampal inoculation of Sup35NM fibrils accentuated tau pathology in P301S tau transgenic mice. Thus, our results provide first in vivo evidence for heterotypic cross-species seeding of a neurodegenerative human prion-like protein by a yeast prion. This opens up the conceptual perspective that non-mammalian prions present in the human microbiome could be involved in the initiation of protein misfolding in neurodegenerative disorders, a mechanism for which we propose the term "trans-seeding."

Keywords: Alzheimer's disease; Sup35; neurodegeneration; prion; seeding; tau; trans-seeding; yeast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Animals
  • Humans
  • Mice
  • Mice, Transgenic
  • Prions* / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Tauopathies* / pathology
  • tau Proteins / metabolism

Substances

  • tau Proteins
  • Prions