Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways.

Tg2576 mice overexpress a mutant form of human amyloid precursor protein with the Swedish mutation (APP(Sw)), resulting in high beta-amyloid (Abeta) levels in the brain. Despite this, amyloid plaques do not develop until 12 months of age, and there is no neuronal loss in mice as old as 16 months. Gene expression profiles in the hippocampus and cerebellum of 6-month-old APP(Sw) mice were compared with age-matched controls. The expression of transthyretin, a protein shown to sequester Abeta and prevent amyloid fibril formation in vitro, and several genes in the insulin-signaling pathway, e.g., insulin-like growth factor-2, were increased selectively in the hippocampus of APP(Sw) mice. Concomitant activation of the insulin-like growth factor-1 receptor, Akt, and extracellular signal-regulated protein kinase 1 and 2 as well as increased phosphorylation of Bad also were unique to the hippocampus of APP(Sw) mice. In addition, the increased expression of transthyretin and insulin-like growth factor-2 and the increased phosphorylation of Bad in hippocampal neurons were maintained in 12-month-old APP(Sw) mice when compared with age-matched controls. These results suggest that the slow progression and lack of full-fledged Alzheimer's disease pathology in the hippocampal neurons of APP(Sw) mice result from the genetic reprogramming of neural cells to cope with increased levels of Abeta.