Syntaxin 5 interacts specifically with presenilin holoproteins and affects processing of βAPP in neuronal cells

The specific roles of syntaxin 5 (Syx 5) in the interaction with presenilin (PS) and the accumulation of β-amyloid precursor protein (βAPP), as well as the secretion of β-amyloid peptide (Aβ peptide) were examined in NG108-15 cells. Syx 5, which localizes from the endoplasmic reticulum (ER) to the Golgi, bound to PS holoproteins, while the other Syxs studied did not. Among familial Alzheimer's disease (FAD)-linked PS mutants, PS1ΔE9, which lacks the endoproteolytic cleavage site, showed markedly decreased binding to Syx 5. The interaction domains in Syx 5 were mapped to the transmembrane region and to the cytoplasmic region containing the α-helical domains, which are distinct from the H3 (SNARE motif). Among all of the Syxs examined, only overexpression of Syx 5 resulted in the accumulation of βAPP in the ER to cis-Golgi compartment, an attenuation of the amount of the C-terminal fragment (APP-CTF) of βAPP, and a reduction in the secretion of Aβ peptides. Furthermore, co-expression of Syx 5 with C99 resulted in an increase in APP-CTF and suppressed Aβ secretion. Taken together, these results indicate that Syx 5 may play a specific role in the modulation of processing and/or trafficking of FAD-related proteins in neuronal cells by interaction with PS holoproteins in the early secretory compartment of neuronal cells.