| First Author | Lundgren JL | Year | 2015 |
| Journal | J Neurochem | Volume | 135 |
| Issue | 3 | Pages | 606-15 |
| PubMed ID | 26296617 | Mgi Jnum | J:227022 |
| Mgi Id | MGI:5699522 | Doi | 10.1111/jnc.13287 |
| Citation | Lundgren JL, et al. (2015) ADAM10 and BACE1 are localized to synaptic vesicles. J Neurochem 135(3):606-15 |
| abstractText | Synaptic degeneration and accumulation of the neurotoxic amyloid beta-peptide (Abeta) in the brain are hallmarks of Alzheimer disease. Abeta is produced by sequential cleavage of the amyloid precursor protein (APP), by the beta-secretase beta-site APP cleaving enzyme 1 (BACE1) and gamma-secretase. However, Abeta generation is precluded if APP is cleaved by the alpha-secretase ADAM10 instead of BACE1. We have previously shown that Abeta can be produced locally at the synapse. To study the synaptic localization of the APP processing enzymes we used western blotting to demonstrate that, compared to total brain homogenate, ADAM10 and BACE1 were greatly enriched in synaptic vesicles isolated from rat brain using controlled-pore glass chromatography, whereas Presenilin1 was the only enriched component of the gamma-secretase complex. Moreover, we detected ADAM10 activity in synaptic vesicles and enrichment of the intermediate APP-C-terminal fragments (APP-CTFs). We confirmed the western blotting findings using in situ proximity ligation assay to demonstrate close proximity of ADAM10 and BACE1 with the synaptic vesicle marker synaptophysin in intact mouse primary hippocampal neurons. In contrast, only sparse co-localization of active gamma-secretase and synaptophysin was detected. These results indicate that the first step of APP processing occurs in synaptic vesicles whereas the final step is more likely to take place elsewhere. The amyloid-beta (Abeta) precursor protein, FL-APP, is cleaved into the synaptotoxic Abeta by BACE1 and gamma-secretase while ADAM10 cleavage precludes Abeta formation. We demonstrate enrichment of ADAM10 and BACE1, but not gamma-secretase, in synaptic vesicles which indicates that the first step of APP processing occurs in synaptic vesicles whereas the final step is more likely to take place elsewhere. |
