APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1

Neurobiol Aging. 2004 Aug;25(7):885-92. doi: 10.1016/j.neurobiolaging.2003.09.008.


More than 70 different mutations in presenilin 1 (PS1) have been associated with inherited early onset Alzheimer's disease (AD). How all these different mutations cause disease has not been clearly delineated. Our laboratory has previously shown that co-expression of mutant PS1 in mice transgenic for amyloid precursor protein (APPswe) dramatically accelerates the rate of amyloid deposition in the brain. In our original animals mutant PS1 was substantially over-expressed, and the stabilized pool of mouse PS1 fragments was largely replaced by the human protein. In this setting the accelerated amyloid pathology in the double transgenic mice could have been due, in part, to decreased endogenous PS1 activity. To investigate this possibility, we generated APP transgenic mice with reduced levels of endogenous PS1. We find that mice harboring only one functional PS1 allele and co-expressing Mo/HuAPPswe do not develop amyloid deposits at ages comparable to mice expressing mutant PS1. We next tested whether hypo-expression of mutant PS1 could accelerate the rate of amyloid deposition using an unusual line of transgenic mice expressing PS1dE9 at low levels, finding no significant acceleration. Our findings demonstrate that the accelerated amyloid pathology, caused by so many different mutations in PS1, is clearly not a result of haplo-insufficiency that might result from inactivating mutations. Instead, our data are consistent with a gain of property mechanism.

Publication types

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

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / physiopathology
  • Amyloid / metabolism*
  • Amyloid beta-Protein Precursor / biosynthesis*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / metabolism*
  • Chimera
  • Disease Models, Animal
  • Female
  • Gene Deletion
  • Gene Expression Regulation / physiology
  • Humans
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Presenilin-1
  • RNA, Messenger / analysis


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