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FASEB J. 2019 Mar;33(3):3758-3771. doi: 10.1096/fj.201801319R. Epub 2018 Nov 27.

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

Author information

1
Biomedical Research Institute of New Jersey, Cedar Knolls, New Jersey, USA.
2
Atlantic Health System, Morristown, New Jersey, USA.
3
Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York, USA.
4
Department of Psychiatry, NYU Langone Medical Center, New York, New York, USA.
5
Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, New York, New York, USA; and.
6
Neuroscience Institute, NYU Langone Medical Center, New York, New York, USA.

Abstract

Accumulating evidence suggests that the abnormal aggregation of amyloid-β (Αβ) peptide in Alzheimer's disease (AD) begins intraneuronally, within vesicles of the endosomal-lysosomal pathway where Aβ 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 Aβ. In this study, we determined whether disruption of Aβ catabolism could trigger Aβ aggregation within neurons and increase the amount of Aβ 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 Aβ levels and promoted the intracellular formation of Aβ oligomers, a process that did not require internalization of secreted Aβ. In vivo, the accumulation of intraneuronal Aβ aggregates was accompanied by increased levels of both extracellular and exosome-associated Aβ, including oligomeric species. Neuronal exosomes were found to contain both ECE-1 and -2 activities, suggesting that multivesicular bodies are intracellular sites of Aβ degradation by these enzymes. ECE dysfunction could lead to the accumulation of intraneuronal Aβ aggregates and their subsequent release into the extracellular space via exosomes.-Pacheco-Quinto, J., Clausen, D., Pérez-González, R., Peng, H., Meszaros, A., Eckman, C. B., Levy, E., Eckman, E. A. Intracellular metalloprotease activity controls intraneuronal Aβ aggregation and limits secretion of Aβ via exosomes.

KEYWORDS:

Alzheimer’s disease; ECE; multivesicular body; oligomer

PMID:
30481490
PMCID:
PMC6404562
DOI:
10.1096/fj.201801319R
[Indexed for MEDLINE]
Free PMC Article

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