The two faces of the amyloid precursor protein
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 β-amyloid (Aβ) 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 Aβ 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 Aβ and sAPPα, which have distinct biological actions. While Aβ can lead to toxicity and cell death, sAPPα promotes neurite outgrowth, enhances memory, and protects against a variety of insults. Here I show that sAPPα induces the expression of transthyretin and insulin-like growth factor 2 in hippocampal slice cultures and can protect against Aβ-induced tau phosphorylation and neuronal death. In AD, the level of Aβ increases while the level of sAPPα decreases. In contrast, APPSw mice possess a dramatically increased level of sAPPα within their hippocampi. Infusion of an anti-transthyretin antibody into the hippocampus of APPSw mice resulted in increased Aβ, tau phosphorylation, and neuronal death and loss. Therefore, the elevated expression of transthyretin is driven by sAPPα 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 Aβ led to tau phosphorylation and neuronal death analogous to what occurs in AD. Pretreatment with sAPPα completely protected against these pathologies. These data demonstrate the dual actions of APP where cleavage to generate sAPPα protects against Aβ-induced neuropathology. Therefore, increased levels of sAPPα and/or transthyretin might delay or prevent the development of AD.