Abstract
The amyloid precursor protein (APP) is well known for giving rise to the amyloid-β peptide and for its role in Alzheimer's disease. Much less is known, however, on the physiological roles of APP in the development and plasticity of the central nervous system. We have used phage display of a peptide library to identify high-affinity ligands of purified recombinant human sAPPα695 (the soluble, secreted ectodomain from the main neuronal APP isoform). Two peptides thus selected exhibited significant homologies with the conserved extracellular domain of several members of the semaphorin (Sema) family of axon guidance proteins. We show that sAPPα695 binds both purified recombinant Sema3A and Sema3A secreted by transfected HEK293 cells. Interestingly, sAPPα695 inhibited the collapse of embryonic chicken (Gallus gallus domesticus) dorsal root ganglia growth cones promoted by Sema3A (Kd≤8·10−9 M). Two Sema3A-derived peptides homologous to the peptides isolated by phage display blocked sAPPα binding and its inhibitory action on Sema3A function. These two peptides are comprised within a domain previously shown to be involved in binding of Sema3A to its cellular receptor, suggesting a competitive mechanism by which sAPPα modulates the biological action of semaphorins.
Highlights
The amyloid precursor protein (APP) family members are ubiquitously expressed type I integral membrane proteins with relatively large extracellular domains and short intracellular domains
We show that sAPPa695 binds with high affinity to semaphorin 3A (Sema3A) and inhibits the collapse of chicken dorsal root ganglia (DRG) growth cones induced by Sema3A
The TFASVMT peptide is homologous to a region of semaphorin 3A (Fig. 1B) that has been shown to be important for receptor recognition [39,40], while the region that is homologous to the LRSHPLG peptide lies very close to that same important site
Summary
The amyloid precursor protein (APP) family members are ubiquitously expressed type I integral membrane proteins with relatively large extracellular domains and short intracellular domains. The secreted extracellular domain of APP, sAPPa, acts as a growth factor for many cell types and promotes neuritogenesis in post-mitotic neurons [5]. Consistent with a physiological role for APP in neuron development [6,7], secreted APP fragments and overexpression of transmembrane APP have both been shown to increase neurite outgrowth [8,9,10], whereas decreased APP expression alters process outgrowth [6,11,12] and APP knock-out mice exhibit motor dysfunction and brain gliosis [6]. Recent data showed that a complex including APP, FE65 and an additional unknown protein is involved in neurite outgrowth at early stages of neuronal development [13]. The mechanisms by which APP regulates neurite outgrowth remain largely unknown
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