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Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice.

The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta 42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta 42 secretion in all mutant clones. Likewise, mutant but not wildtype PS1 transgenic mice showed significant overproduction of A beta 42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta 42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta 42 production, thus promoting cerebral beta-amyloidosis.

Pubmed ID: 8986743

Authors

  • Citron M
  • Westaway D
  • Xia W
  • Carlson G
  • Diehl T
  • Levesque G
  • Johnson-Wood K
  • Lee M
  • Seubert P
  • Davis A
  • Kholodenko D
  • Motter R
  • Sherrington R
  • Perry B
  • Yao H
  • Strome R
  • Lieberburg I
  • Rommens J
  • Kim S
  • Schenk D
  • Fraser P
  • St George Hyslop P
  • Selkoe DJ

Journal

Nature medicine

Publication Data

January 31, 1997

Associated Grants

  • Agency: Canadian Institutes of Health Research, Id: 64309
  • Agency: NIA NIH HHS, Id: AG 06173
  • Agency: NIA NIH HHS, Id: AG 106812
  • Agency: NIA NIH HHS, Id: AG 12749

Mesh Terms

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Animals
  • Brain
  • Cell Line
  • Enzyme-Linked Immunosorbent Assay
  • Genetic Vectors
  • Hippocampus
  • Humans
  • Membrane Proteins
  • Mice
  • Mice, Transgenic
  • Mutation
  • Peptide Fragments
  • Presenilin-1
  • Presenilin-2
  • Transfection