Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau

Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13896-901. doi: 10.1073/pnas.202205599. Epub 2002 Oct 4.


The R406W tau mutation found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) causes a hereditary tauopathy clinically resembling Alzheimer's disease. Expression of modest levels of the longest human tau isoform with this mutation under the control of the alpha-calcium-calmodulin-dependent kinase-II promoter in transgenic (Tg) mice resulted in the development of congophilic hyperphosphorylated tau inclusions in forebrain neurons. These inclusions appeared as early as 18 months of age. As with human cases, tau inclusions were composed of both mutant and endogenous wild-type tau, and were associated with microtubule disruption and flame-shaped transformations of the affected neurons. Straight tau filaments were recovered from Sarkosyl-insoluble fractions from only the aged Tg brains. Behaviorally, aged Tg mice had associative memory impairment without obvious sensorimotor deficits. Therefore, these mice that exhibit a phenotype mimicking R406W FTDP-17 provide an animal model for investigating the adverse properties associated with this mutation, which might potentially recapitulate some etiological events in Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism
  • Aging / psychology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / psychology
  • Animals
  • Association Learning / physiology
  • Disease Models, Animal
  • Gene Expression
  • Humans
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Memory Disorders / genetics*
  • Memory Disorders / metabolism
  • Memory Disorders / psychology*
  • Mice
  • Mice, Transgenic
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Phenotype
  • Point Mutation
  • Prosencephalon / metabolism
  • Prosencephalon / pathology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • tau Proteins / chemistry
  • tau Proteins / genetics*
  • tau Proteins / metabolism*


  • Recombinant Proteins
  • tau Proteins