Accelerated human mutant tau aggregation by knocking out murine tau in a transgenic mouse model

Am J Pathol. 2011 Feb;178(2):803-16. doi: 10.1016/j.ajpath.2010.10.034.

Abstract

Many models of human tauopathies have been generated in mice by expression of a human mutant tau with maintained expression of mouse endogenous tau. Because murine tau might interfere with the toxic effects of human mutant tau, we generated a model in which a pathogenic human tau protein is expressed in the absence of wild-type tau protein, with the aim of facilitating the study of the pathogenic role of the mutant tau and to reproduce more faithfully a human tauopathy. The Tg30 line is a tau transgenic mouse model overexpressing human 1N4R double-mutant tau (P301S and G272V) that develops Alzheimer's disease-like neurofibrillary tangles in an age-dependent manner. By crossing Tg30 mice with mice invalidated for their endogenous tau gene, we obtained Tg30xtau(-/-) mice that express only exogenous human double-mutant 1N4R tau. Although Tg30xtau(-/-) mice express less tau protein compared with Tg30, they exhibit signs of decreased survival, increased proportion of sarkosyl-insoluble tau in the brain and in the spinal cord, increased number of Gallyas-positive neurofibrillary tangles in the hippocampus, increased number of inclusions in the spinal cord, and a more severe motor phenotype. Deletion of murine tau accelerated tau aggregation during aging of this mutant tau transgenic model, suggesting that murine tau could interfere with the development of tau pathology in transgenic models of human tauopathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Gene Knockout Techniques*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Intranuclear Inclusion Bodies / drug effects
  • Intranuclear Inclusion Bodies / pathology
  • Intranuclear Inclusion Bodies / ultrastructure
  • Memory, Short-Term / drug effects
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism*
  • Models, Animal
  • Motor Activity / drug effects
  • Mutant Proteins / chemistry*
  • Mutant Proteins / metabolism*
  • Neurofibrillary Tangles / drug effects
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Neurofibrillary Tangles / ultrastructure
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Structure, Quaternary
  • Sarcosine / analogs & derivatives
  • Sarcosine / pharmacology
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / pathology
  • Solubility / drug effects
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Survival Analysis
  • tau Proteins / chemistry
  • tau Proteins / metabolism*

Substances

  • MAPT protein, human
  • Mapt protein, mouse
  • Microtubule-Associated Proteins
  • Mutant Proteins
  • tau Proteins
  • sarkosyl
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Sarcosine