| First Author | Pacheco-Quinto J | Year | 2019 |
| Journal | FASEB J | Volume | 33 |
| Issue | 3 | Pages | 3758-3771 |
| PubMed ID | 30481490 | Mgi Jnum | J:287245 |
| Mgi Id | MGI:6391327 | Doi | 10.1096/fj.201801319R |
| Citation | Pacheco-Quinto J, et al. (2019) Intracellular metalloprotease activity controls intraneuronal Abeta aggregation and limits secretion of Abeta via exosomes. FASEB J 33(3):3758-3771 |
| abstractText | Accumulating evidence suggests that the abnormal aggregation of amyloid-beta (Alphabeta) peptide in Alzheimer's disease (AD) begins intraneuronally, within vesicles of the endosomal-lysosomal pathway where Abeta is both generated and degraded. Metalloproteases, including endothelin-converting enzyme (ECE)-1 and -2, reside within these vesicles and normally limit the accumulation of intraneuronally produced Abeta. In this study, we determined whether disruption of Abeta catabolism could trigger Abeta aggregation within neurons and increase the amount of Abeta associated with exosomes, small extracellular vesicles derived from endosomal multivesicular bodies. Using cultured cell lines, primary neurons, and organotypic brain slices from an AD mouse model, we found that pharmacological inhibition of the ECE family of metalloproteases increased intracellular and extracellular Abeta levels and promoted the intracellular formation of Abeta oligomers, a process that did not require internalization of secreted Abeta. In vivo, the accumulation of intraneuronal Abeta aggregates was accompanied by increased levels of both extracellular and exosome-associated Abeta, including oligomeric species. Neuronal exosomes were found to contain both ECE-1 and -2 activities, suggesting that multivesicular bodies are intracellular sites of Abeta degradation by these enzymes. ECE dysfunction could lead to the accumulation of intraneuronal Abeta aggregates and their subsequent release into the extracellular space via exosomes.-Pacheco-Quinto, J., Clausen, D., Perez-Gonzalez, R., Peng, H., Meszaros, A., Eckman, C. B., Levy, E., Eckman, E. A. Intracellular metalloprotease activity controls intraneuronal Abeta aggregation and limits secretion of Abeta via exosomes. |
