| First Author | Gautam V | Year | 2015 |
| Journal | Mol Neurodegener | Volume | 10 |
| Pages | 31 | PubMed ID | 26202512 |
| Mgi Jnum | J:345364 | Mgi Id | MGI:6838777 |
| Doi | 10.1186/s13024-015-0028-5 | Citation | Gautam V, et al. (2015) Synaptotagmins interact with APP and promote Abeta generation. Mol Neurodegener 10:31 |
| abstractText | BACKGROUND: Accumulation of the beta-amyloid peptide (Abeta) is a major pathological hallmark of Alzheimer's disease (AD). Recent studies have shown that synaptic Abeta toxicity may directly impair synaptic function. However, proteins regulating Abeta generation at the synapse have not been characterized. Here, we sought to identify synaptic proteins that interact with the extracellular domain of APP and regulate Abeta generation. RESULTS: Affinity purification-coupled mass spectrometry identified members of the Synaptotagmin (Syt) family as novel interacting proteins with the APP ectodomain in mouse brains. Syt-1, -2 and -9 interacted with APP in cells and in mouse brains in vivo. Using a GST pull-down approach, we have further demonstrated that the Syt interaction site lies in the 108 amino acids linker region between the E1 and KPI domains of APP. Stable overexpression of Syt-1 or Syt-9 with APP in CHO and rat pheochromocytoma cells (PC12) significantly increased APP-CTF and sAPP levels, with a 2 to 3 fold increase in secreted Abeta levels in PC12 cells. Moreover, using a stable knockdown approach to reduce the expression of endogenous Syt-1 in PC12 cells, we have observed a ~ 50% reduction in secreted Abeta generation. APP processing also decreased in these cells, shown by lower CTF levels. Lentiviral-mediated knock down of endogenous Syt-1 in mouse primary neurons also led to a significant reduction in both Abeta40 and Abeta42 generation. As secreted sAPPbeta levels were significantly reduced in PC12 cells lacking Syt-1 expression, our results suggest that Syt-1 regulates Abeta generation by modulating BACE1-mediated cleavage of APP. CONCLUSION: Altogether, our data identify the synaptic vesicle proteins Syt-1 and 9 as novel APP-interacting proteins that promote Abeta generation and thus may play an important role in the pathogenesis of AD. |
