• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice.

Missense mutations in the beta-amyloid precursor protein gene (APP) co-segregate with a small subset of autosomal dominant familial Alzheimer's disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid (A beta) peptide and neurodegeneration are principal neuropathological hallmarks. To accurately examine the effect of missense mutations on APP metabolism and A beta production in vivo, we have introduced yeast artificial chromosomes (YACs) containing the entire approximately 400 kbp human APP gene encoding APP harboring either the asparagine for lysine and leucine for methionine FAD substitution at codons 670 and 671 (APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717 (APP(V7171)) or a combination of both substitutions into transgenic mice. We demonstrate that, relative to YAC transgenic mice expressing wild-type APP, high levels of A beta peptides are detected in the brains of YAC transgenic mice expressing human APP(K670N/M671L) that is associated with a concomitant diminution in the levels of apha-secretase-generated soluble APP derivatives. Moreover, the levels of longer A beta peptides (species terminating at amino acids 42/43) are elevated in YAC transgenic mice expressing human APP(V7171). These mice should prove valuable for detailed analysis of the in vivo effects of the APP FAD mutations in a variety of tissues and throughout aging and for testing therapeutic agents that specifically alter APP metabolism and A beta production.

Pubmed ID: 9285791

Authors

  • Lamb BT
  • Call LM
  • Slunt HH
  • Bardel KA
  • Lawler AM
  • Eckman CB
  • Younkin SG
  • Holtz G
  • Wagner SL
  • Price DL
  • Sisodia SS
  • Gearhart JD

Journal

Human molecular genetics

Publication Data

September 2, 1997

Associated Grants

  • Agency: NIA NIH HHS, Id: AG05146
  • Agency: NICHD NIH HHS, Id: HD24605
  • Agency: NINDS NIH HHS, Id: NS20471

Mesh Terms

  • Alzheimer Disease
  • Amyloid beta-Protein Precursor
  • Animals
  • Cell Culture Techniques
  • Chromosomes, Artificial, Yeast
  • Gene Expression
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutagenesis
  • Polymerase Chain Reaction
  • RNA, Messenger
  • Transgenes