| First Author | Das U | Year | 2016 |
| Journal | Nat Neurosci | Volume | 19 |
| Issue | 1 | Pages | 55-64 |
| PubMed ID | 26642089 | Mgi Jnum | J:234437 |
| Mgi Id | MGI:5790014 | Doi | 10.1038/nn.4188 |
| Citation | Das U, et al. (2016) Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nat Neurosci 19(1):55-64 |
| abstractText | Cleavage of amyloid precursor protein (APP) by BACE-1 (beta-site APP cleaving enzyme-1) is the rate-limiting step in amyloid-beta (Abeta) production and a neuropathologic hallmark of Alzheimer's disease; thus, physical approximation of this substrate-enzyme pair is a crucial event with broad biological and therapeutic implications. Despite much research, neuronal locales of APP and BACE-1 convergence and APP cleavage remain unclear. Here we report an optical assay, based on fluorescence complementation, for visualizing in cellulo APP-BACE-1 interactions as a simple on/off signal. Combining this with other assays tracking the fate of internalized APP in hippocampal neurons, we found that APP and BACE-1 interacted in both biosynthetic and endocytic compartments, particularly along recycling microdomains such as dendritic spines and presynaptic boutons. In axons, APP and BACE-1 were cotransported, and they also interacted during transit. Finally, our assay revealed that the Alzheimer's disease-protective 'Icelandic' mutation greatly attenuates APP-BACE-1 interactions, suggesting a mechanistic basis for protection. Collectively, the data challenge canonical models and provide concrete insights into long-standing controversies in the field. |
