Secreted Amyloid Precursor Protein β and Secreted Amyloid Precursor Protein α Induce Axon Outgrowth In Vitro through Egr1 Signaling Pathway

Background: sAPP alpha released after alpha secretase cleavage of Amyloid Precursor Protein (APP) has several functions including the stimulation of neurite outgrowth although detailed morphometric analysis has not been done. Two domains involved in this function have been described and are present in sAPP beta released at the first step of amyloid peptide cleavage, raising the possibility that sAPP beta could also stimulate neurite outgrowth. We investigated the morphological effects of sAPP alpha and sAPP beta on primary neurons and identified a key signaling event required for the changes observed. Methodology/Principal Findings: Final concentrations of 50 to 150 nM bacterial recombinant sAPP alpha or sAPP beta added to primary neuronal cultures after 1 day in vitro decreased cell adhesion 24 hours later and primary dendrite length 96 hours later. 150 nM sAPP alpha and sAPP beta induced a similar increase of axon outgrowth, although this increase was already significant at 100 nM sAPP alpha. These morphological changes induced by sAPPs were also observed when added to differentiated neurons at 5 days in vitro. Real time PCR and immunocytochemistry showed that sAPP alpha and sAPP beta stimulated Egr1 expression downstream of MAPK/ERK activation. Furthermore, in primary neurons from Egr1 -/- mice, sAPPs affected dendritic length but did not induce any increase of axon length. Conclusion/Significance: sAPP alpha and sAPP beta decrease cell adhesion and increase axon elongation. These morphological changes are similar to what has been observed in response to heparan sulfate. The sAPP alpha/sAPP beta stimulated increase in axon growth requires Egr1 signaling. These data suggest that sAPP beta is not deleterious per se. Since sAPP beta and sAPP alpha are present in the embryonic brain, these two APP metabolites might play a role in axon outgrowth during development and in response to brain damage.