Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Kuzuya, Akira; Zoltowska, Katarzyna; Post, Kathryn; Arimon, Muriel; Li, Xuejing; Svirsky, Sarah; Maesako, Masato; Muzikansky, Alona; Gautam, Vivek; Kovacs, Dora; Hyman, Bradley; Berezovska, Oksana
• Is Part Of: BMC biology. Volume 14:Issue 1(2016)
• Page Start: 1
• Page End: 24
• Publication Date: 2016-12
• Subjects: Synaptotagmin 1 -- Presenilin 1 -- Alzheimer's disease -- Beta amyloid; Biology -- Periodicals; Medical sciences -- Periodicals; Biomedical Research -- Periodicals; 570.5
• DOI: 10.1186/s12915-016-0248-3
• Languages: English
• ISSNs: 1741-7007

Abstract

Abstract Background 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.