title: Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice.
abstract: 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.
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA. btl@po.cwru.edu
authors.forename: B T
authors.initials: BT
authors.lastname: Lamb
authors.forename: L M
authors.initials: LM
authors.lastname: Call
authors.forename: H H
authors.initials: HH
authors.lastname: Slunt
authors.forename: K A
authors.initials: KA
authors.lastname: Bardel
authors.forename: A M
authors.initials: AM
authors.lastname: Lawler
authors.forename: C B
authors.initials: CB
authors.lastname: Eckman
authors.forename: S G
authors.initials: SG
authors.lastname: Younkin
authors.forename: G
authors.initials: G
authors.lastname: Holtz
authors.forename: S L
authors.initials: SL
authors.lastname: Wagner
authors.forename: D L
authors.initials: DL
authors.lastname: Price
authors.forename: S S
authors.initials: SS
authors.lastname: Sisodia
authors.forename: J D
authors.initials: JD
authors.lastname: Gearhart
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018929:Cell Culture Techniques; D018244:Chromosomes, Artificial, Yeast; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D016296:Mutagenesis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D012333:RNA, Messenger