Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease

Neurobiol Aging. 2003 Dec;24(8):1063-70. doi: 10.1016/j.neurobiolaging.2003.08.012.


Amyloid-beta (Abeta) containing plaques and tau-laden neurofibrillary tangles are the defining neuropathological features of Alzheimer's disease (AD). To better mimic this neuropathology, we generated a novel triple transgenic model of AD (3xTg-AD) harboring three mutant genes: beta-amyloid precursor protein (betaAPPSwe), presenilin-1 (PS1M146V), and tauP301L. The 3xTg-AD mice progressively develop Abeta and tau pathology, with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We find that Abeta deposits initiate in the cortex and progress to the hippocampus with aging, whereas tau pathology is first apparent in the hippocampus and then progresses to the cortex. Despite equivalent overexpression of the human betaAPP and human tau transgenes, Abeta deposition develops prior to the tangle pathology, consistent with the amyloid cascade hypothesis. As these 3xTg-AD mice phenocopy critical aspects of AD neuropathology, this model will be useful in pre-clinical intervention trials, particularly because the efficacy of anti-AD compounds in mitigating the neurodegenerative effects mediated by both signature lesions can be evaluated.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / metabolism
  • Brain / pathology*
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Membrane Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Neurofibrillary Tangles / genetics
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology*
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology*
  • Presenilin-1
  • tau Proteins / genetics


  • Amyloid beta-Protein Precursor
  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • tau Proteins