Affiliations: [a] Fundación Instituto Leloir, IIBBA-CONICET, Ciudad de Buenos Aires, Argentina | [b] Center for Neuroscience and Aging, The Burnham Institute for Medical Research, La Jolla, CA, USA | Sanders-Brown Center on Aging and Alzheimer's Disease Center, Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA
Correspondence:
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Corresponding author: Laura Morelli, Fundación Instituto Leloir, IIBBA-CONICET, Ave. Patricias Argentinas 435, Ciudad de Buenos Aires C1405BWE, Argentina. Tel.: +54 11 5238 7500; Fax: +54 11 5238 7501; E-mail: [email protected]
Note: [1] Contributed equally to this work.
Abstract: The accumulation of amyloid-β (Aβ) peptides in senile plaques is one of the hallmarks of Alzheimer's disease (AD) progression. The endocytic pathway has been proposed as a major subcellular site for Aβ generation while the compartments in which Aβ-degrading proteases interact with Aβ are still elusive. It was suggested that extracellular Aβ degradation may take place by plasma-membrane associated proteases or by extracellular proteases, among which insulin-degrading enzyme (IDE) is the most relevant. However, the mechanisms of IDE secretion are poorly understood. In the present study we used N2a cells to explore if IDE is indeed released through exosomes and the effect of exosomes release on extracellular levels of Aβ. We demonstrated that proteolytically-active plasma membrane associated-IDE is routed in living N2a cells to multivesicular bodies and subsequently, a major fraction is sorted to exosomes. We described that extracellular IDE levels decrease if the generation of multivesicular bodies is interfered and may be positively modulated by exosomes release under stress-induced conditions. Our results reinforce the relevance of functional IDE in the catabolism of extracellular Aβ.
