Kuzuya, AkiraZoltowska, KatarzynaPost, Kathryn L.Arimon, MurielLi, XuejingSvirsky, SarahMaesako, MasatoMuzikansky, AlonaGautam, VivekKovacs, DoraHyman, BradleyBerezovska, Oksana2016-05-022016Kuzuya, A., K. M. Zoltowska, K. L. Post, M. Arimon, X. Li, S. Svirsky, M. Maesako, et al. 2016. “Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta.” BMC Biology 14 (1): 25. doi:10.1186/s12915-016-0248-3. http://dx.doi.org/10.1186/s12915-016-0248-3.1741-7007http://nrs.harvard.edu/urn-3:HUL.InstRepos:26859875Background: Synaptic loss strongly correlates with memory deterioration. Local accumulation of amyloid β (Aβ) peptide, and neurotoxic Aβ42 in particular, due to abnormal neuronal activity may underlie synaptic dysfunction, neurodegeneration, and memory impairments. To gain an insight into molecular events underlying neuronal activity-regulated Aβ production at the synapse, we explored functional outcomes of the newly discovered calcium-dependent interaction between Alzheimer’s disease-associated presenilin 1 (PS1)/γ-secretase and synaptic vesicle proteins. Results: Mass spectrometry screen of mouse brain lysates identified synaptotagmin 1 (Syt1) as a novel synapse-specific PS1-binding partner that shows Ca2+-dependent PS1 binding profiles in vitro and in vivo. We found that Aβ level, and more critically, conformation of the PS1 and the Aβ42/40 ratio, are affected by Syt1 overexpression or knockdown, indicating that Syt1 and its interaction with PS1 might regulate Aβ production at the synapse. Moreover, β-secretase 1 (BACE1) stability, β- and γ-secretase activity, as well as intracellular compartmentalization of PS1 and BACE1, but not of amyloid precursor protein (APP), nicastrin (Nct), presenilin enhancer 2 (Pen-2), or synaptophysin (Syp) were altered in the absence of Syt1, suggesting a selective effect of Syt1 on PS1 and BACE1 trafficking. Conclusions: Our findings identify Syt1 as a novel Ca2+-sensitive PS1 modulator that could regulate synaptic Aβ, opening avenues for novel and selective synapse targeting therapeutic strategies. Electronic supplementary material The online version of this article (doi:10.1186/s12915-016-0248-3) contains supplementary material, which is available to authorized users.en-USSynaptotagmin 1Presenilin 1Alzheimer’s diseaseBeta amyloidJournal Article2016-05-0210.1186/s12915-016-0248-3