Functions of Aß, sAPPa and sAPPß: similarities and differences

Amyloid peptide (A beta) is derived from the cleavage of amyloid precursor protein (APP), which also generates the soluble peptide APP beta (sAPP beta). An antagonist and major APP metabolic pathway involves cleavage by alpha secretase, which releases sAPPa. Although soluble A beta oligomers are neurotoxic, A beta monomers share similar properties with sAPPa. These include neurotrophic and neuroprotective effects, as well as stimulation of neural-progenitor proliferation. The properties of A beta monomers and the neurotrophic capacity of sAPP beta to stimulate axonal outgrowth suggest that A beta production is not deleterious per se. Consequently, therapeutic strategies for Alzheimers disease that are targeted at A beta-cleaving enzymes should modulate rather than inhibit A beta generation. These strategies should focus on the factors that induce the conversion of A beta monomers into toxic soluble oligomers. Another interesting therapeutic approach is to focus on the mechanisms of the different properties of sAPPa. Indeed, increasing sAPPa levels could shift proliferating cells towards tumorigenesis. In contrast to its neuroprotective effects, sAPPa is also able to activate microglia, leading to neurotoxicity. Understanding the mechanisms that underlie the different properties of sAPPa could therefore lead to the development of therapeutic strategies against Alzheimers disease, which could be curative as well as preventive.