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

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  • Athanasios Metaxas, Univ Southern Denmark, University of Southern Denmark, Inst Mol Med
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  • Camilla Thygesen, Univ Southern Denmark, University of Southern Denmark, Inst Mol Med, Univ Southern Denmark, University of Southern Denmark, Dept Biochem & Mol Biol
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  • Stefan J. Kempf, Univ Southern Denmark, University of Southern Denmark, Dept Biochem & Mol Biol
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  • Marco Anzalone, Univ Southern Denmark, University of Southern Denmark, Inst Mol Med
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  • Ramanan Vaitheeswaran, Univ Southern Denmark, University of Southern Denmark, Inst Mol Med
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  • Sussanne Petersen, Univ Southern Denmark, University of Southern Denmark, Inst Mol Med
  • ,
  • Anne M. Landau
  • Helene Audrain
  • Jessica L. Teeling, Univ Southampton, University of Southampton, Southampton Gen Hosp, Biol Sci
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  • 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
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  • Bente Finsen, Univ Southern Denmark, University of Southern Denmark, Inst Mol Med

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
Volume9
Number of pages15
ISSN2045-2322
DOIs
Publication statusPublished - 31 Oct 2019

    Research areas

  • POSITRON-EMISSION-TOMOGRAPHY, PAIRED HELICAL FILAMENTS, NEUROFIBRILLARY TANGLES, HUMAN BRAIN, PROTEIN, BETA, MICE, ISOFORMS, IMMUNOHISTOCHEMISTRY, PHOSPHORYLATION

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