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

Missense mutations in the β-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 β-amyloid (Aβ) peptide and neurodegeneration are principal neuropathological hallmarks. To accurately examine the effect of missense mutations on APP metabolism and Aβ production in vivo, we have introduced yeast artificial chromosomes (YACs) containing the entire ~ 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(V717I)) or a combination of both substitutions into transgenic mice. We demonstrate that, relative to YAC transgenic mice expressing wild-type APP, high levels of Aβ 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 α-secretase-generated soluble APP derivatives. Moreover, the levels of longer Aβ peptides (species terminating at amino acids 42/43) are elevated in YAC transgenic mice expressing human APP(V717I). 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 Aβ production.