Mice engineered to overexpress diseasecausing mutant amyloid precursor proteins (APP) display plaque deposition, but lack the hyperphosphorylated tau and massive neuronal loss characteristic of Alzheimer's disease (AD). Global gene expression profiles of brain regions from AD patients show upregulation of proapoptotic and inflammatory genes and downregulation of neurotrophic, MAPK, phosphatase, and synaptic genes, while a profile of mice overexpressing a mutant APP shows the opposite trends in apoptotic and neurotrophic genes. The proteolytic fragments of the amyloid precursor protein have distinct biological actions. Both the γ-secretase cleaved COOH-terminal fragment (CTFy) and the a-secretase cleaved NH2-terminal of APP (sAPPa) can regulate gene expression. While Aß and CTFy can lead to toxicity and cell death, sAPPa promotes neurite outgrowth, enhances memory, and protects against a variety of insults, including Aß toxicity. In AD, Aß levels increase while sAPPa levels decrease. These subtleties in the levels of APP cleavage products are not reproduced in mice overexpressing mutant APP. In fact, the gene expression changes driven by sAPPa, such as increases in transthyretin and insulin-like growth factor 2, may protect these mice from high levels of Aß.