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'sdisease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid(A beta) peptide and neurodegeneration are principal neuropathologicalhallmarks. To accurately examine the effect of missense mutations on APPmetabolism and A beta production in vivo, we have introduced yeastartificial chromosomes (YACs) containing the entire approximately 400 kbphuman APP gene encoding APP harboring either the asparagine for lysine andleucine 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-typeAPP, high levels of A beta peptides are detected in the brains of YACtransgenic mice expressing human APP(K670N/M671L) that is associated with aconcomitant diminution in the levels of apha-secretase-generated solubleAPP derivatives. Moreover, the levels of longer A beta peptides (speciesterminating at amino acids 42/43) are elevated in YAC transgenic miceexpressing human APP(V7171). These mice should prove valuable for detailedanalysis of the in vivo effects of the APP FAD mutations in a variety oftissues and throughout aging and for testing therapeutic agents thatspecifically alter APP metabolism and A beta production.