Lifespan Profiles of Alzheimer's Disease-Associated Genes and Products in Monkeys and Mice

Alzheimer's disease (AD) is characterized by plaques of amyloid-beta (A beta) peptide, cleaved from amyloid-beta protein precursor (A beta PP). Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of A beta PP mRNA, A beta PP protein, and A beta levels in rodents and primates. We also tracked a transcriptional regulator of the A beta PP gene, specificity protein 1 (SP1), and the beta amyloid precursor cleaving enzyme (BACE1). In mice, A beta PP and SP1 mRNA and their protein products were elevated late in life; A beta levels declined in old age. In monkeys, SP1, A beta PP, and BACE1 mRNA declined in old age, while protein products and A beta levels rose. Proteolytic processing in both species did not match production of A beta. In primates, A beta PP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as A beta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases.