Production and Functional Assays of Recombinant Secreted Amyloid Precursor Protein (APP) (sAPPα)

Abstract

The β-amyloid precursor protein (APP) is connected to Alzheimer’s disease by both biochemistry and genetics. As the source of the major constituent of amyloid plaques, APP has been the subject of many studies of its expression and metabolism. The accumulation of amyloid β-peptide (Aβ) in these plaques was the first evidence that APP might be processed abnormally in Alzheimer’s, and this idea was strengthened by the discovery of mutations in APP that segregate with the disease with high penetrance. Aberrant processing of APP was incorporated into the Amyloid Hypothesis, which supposes that the clinical symptoms, neuropathology, and ultimate fatality of Alzheimer’s result from the actions of Aβ. But to the extent that the Amyloid Hypothesis remains hypothetical, it would be irresponsible to ignore other theories that might explain the links between APP and Alzheimer’s. APP can be proteolytically processed in a way that does not produce (and, in fact, precludes) Aβ. This “α-secretase” event cleaves within the Aβ sequence and liberates most of the extracellular portion (sAPPα) of APP from the cell surface Fig. 1). Because the “β-secretase” event required for the generation of Aβ creates a different soluble derivative (sAPPβ), disease-related increases in β-secretase processing —such as demonstrated with the “Swedish” mutation of APP—have the potential to affect events dependent on the normal function(s) of sAPPα. Furthermore, the increases in APP expression that occur as a result of injury or trisomy 21 may elevate the total levels of all sAPP species. To understand the implications of these events, it is critical to elucidate the biological activities of sAPPα and related moieties.