Synapsin 1 promotes Aβ generation via BACE1 modulation.

It has been revealed that β-amyloid (Aβ) is generated and released from the presynaptic terminals in activity-dependent manner. However, molecules modulating the presynaptic Aβ generation remain elusive. Here we test the hypothesis that Synapsin 1 (Syn1) may acts as a modulator of the Aβ production. Using biochemical and Förster resonance energy transfer (FRET)-based imaging approaches we have found that Syn1 knock down decreases, whereas (over)expression of Syn1 in cells increases the Aβ levels. Mechanistically, Syn1 does not seem to affect the activity of Presenilin 1 (PS1)/γ-secretase, PS1 conformation, or the proximity between PS1 and amyloid precursor protein (APP). However, we found that Syn1 is involved in up-regulation of the β-site APP cleaving enzyme 1 (BACE1)/β-secretase activity and increases the APP/BACE1 interaction. Therefore, we conclude that Syn1 may promote Aβ production via the modulation of BACE1.