Intracellular metalloprotease activity controls intraneuronal Aβ aggregation and limits secretion of Aβ via exosomes.

Accumulating evidence suggests that the abnormal aggregation of amyloid- () peptide in Alzheimer's disease (AD) begins intraneuronally, within vesicles of the endosomal-lysosomal pathway where A 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 A. In this study, we determined whether disruption of A catabolism could trigger A aggregation within neurons and increase the amount of A 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 A levels and promoted the intracellular formation of A oligomers, a process that did not require internalization of secreted A. In vivo, the accumulation of intraneuronal A aggregates was accompanied by increased levels of both extracellular and exosome-associated A, including oligomeric species. Neuronal exosomes were found to contain both ECE-1 and -2 activities, suggesting that multivesicular bodies are intracellular sites of A degradation by these enzymes. ECE dysfunction could lead to the accumulation of intraneuronal A 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 A aggregation and limits secretion of A via exosomes.