| Alzheimer's disease (AD) is the most common cause of senile dementia. Mutations in the amyloid precursor protein (APP) can lead to the disease in humans. However, mice engineered to overexpress mutant APP display beta-amyloid (Abeta) plaque deposition, but lack the hyperphosphorylated tau and massive neuronal loss characteristic of AD. Gene and protein expression in brain regions from AD patients demonstrate an up-regulation of proapoptotic and inflammatory genes and down-regulation of neurotrophic, MAPK, phosphatase, and synaptic genes. In contrast, gene expression in mice overexpressing a mutant APP (APP Sw) shows the opposite trends in apoptotic and neurotrophic genes. In addition, transthyretin, a protein shown to sequester Abeta and prevent amyloid fibril formation in vitro, and insulin-like growth factor 2 are markedly up-regulated in APPSw mice.; The proteolytic fragments of APP include Abeta and sAPPalpha, which have distinct biological actions. While Abeta can lead to toxicity and cell death, sAPPalpha promotes neurite outgrowth, enhances memory, and protects against a variety of insults. Here I show that sAPPalpha induces the expression of transthyretin and insulin-like growth factor 2 in hippocampal slice cultures and can protect against Abeta-induced tau phosphorylation and neuronal death. In AD, the level of Abeta increases while the level of sAPPalpha decreases. In contrast, APPSw mice possess a dramatically increased level of sAPPalpha within their hippocampi. Infusion of an anti-transthyretin antibody into the hippocampus of APPSw mice resulted in increased Abeta, tau phosphorylation, and neuronal death and loss. Therefore, the elevated expression of transthyretin is driven by sAPPalpha and protects APPSw mice from developing many of the neuropathologies observed in AD.; Organotypic slices of the temporal cortex removed during surgery from adult humans were maintained in culture for 4 to 21 days and were shown to possess a healthy population of neurons. Treatment with Abeta led to tau phosphorylation and neuronal death analogous to what occurs in AD. Pretreatment with sAPPalpha completely protected against these pathologies. These data demonstrate the dual actions of APP where cleavage to generate sAPPalpha protects against Abeta-induced neuropathology. Therefore, increased levels of sAPPalpha and/or transthyretin might delay or prevent the development of AD. |
