Aarhus University Seal / Aarhus Universitets segl

Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer's disease

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Athanasios Metaxas, University of Southern Denmark
  • ,
  • Camilla Thygesen, University of Southern Denmark, Univ Southern Denmark, University of Southern Denmark, Dept Biochem & Mol Biol
  • ,
  • Stefan J. Kempf, Univ Southern Denmark, University of Southern Denmark, Dept Biochem & Mol Biol
  • ,
  • Marco Anzalone, University of Southern Denmark
  • ,
  • Ramanan Vaitheeswaran, University of Southern Denmark
  • ,
  • Sussanne Petersen, University of Southern Denmark
  • ,
  • Anne M. Landau
  • Helene Audrain
  • Jessica L. Teeling, University of Southampton
  • ,
  • Sultan Darvesh, Dalhousie Univ, Dalhousie University, Dept Med Neurol & Geriatr Med
  • ,
  • David J. Brooks
  • Martin R. Larsen, Univ Southern Denmark, University of Southern Denmark, Dept Biochem & Mol Biol
  • ,
  • Bente Finsen, University of Southern Denmark

Despite compelling evidence that the accumulation of amyloid-beta (A beta) promotes neocortical MAPT (tau) aggregation in familial and idiopathic Alzheimer's disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. In the present study, we show that tau can accumulate spontaneously in aged transgenic APP(swe)/PS1(Delta E9) mice. Tau pathology is abundant around A beta deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the APP(swe)/PS1(Delta E9) brain at 18 months of age. Age-dependent increases in argyrophilia correlated positively with binding levels of the paired helical filament (PHF) tracer [F-18]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Quantitative proteomics identified sequences of hyperphosphorylated and three-repeat tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Tissue from the frontal gyrus of human subjects was used to validate these findings, revealing primarily quantitative differences between the tau pathology observed in AD patient vs. transgenic mouse tissue. As physiological levels of endogenous, 'wild-type' tau aggregate secondarily to A beta in APP(swe)/PS1(Delta E9) mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.

Original languageEnglish
Article number15758
JournalScientific Reports
Number of pages15
Publication statusPublished - 31 Oct 2019

    Research areas


See relations at Aarhus University Citationformats

ID: 171570139