Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes

Nat Med. 1998 Jan;4(1):97-100. doi: 10.1038/nm0198-097.


Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposits in the cortex and hippocampus. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide A beta42(43). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in A beta42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a "Y" maze before substantial A beta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.

Publication types

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

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Protein Precursor / biosynthesis
  • Amyloid beta-Protein Precursor / genetics*
  • Analysis of Variance
  • Animals
  • Brain / pathology
  • Cerebral Cortex / pathology
  • Crosses, Genetic
  • Genotype
  • Glial Fibrillary Acidic Protein / analysis
  • Humans
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Transgenic
  • Motor Activity
  • Posture
  • Presenilin-1
  • Psychomotor Performance
  • Reflex
  • Seizures


  • Amyloid beta-Protein Precursor
  • Glial Fibrillary Acidic Protein
  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1