Intracellular Cleavage of Amyloid beta by a Viral Protease NIa Prevents Amyloid beta-Mediated Cytotoxicity

Abstract

Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid beta (A beta) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral A beta levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known A beta-cleaving protease, on oligomeric A beta-induced cell death were evaluated. NIa cleaved monomeric and oligomeric A beta at a similar rate, whereas NEP only cleaved monomeric A beta. Oligomeric A beta-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled A beta localized to mitochondria, and this was significantly reduced by NIa, but not by NEP. These data suggest that NIa may exerts its protective roles by degrading Ab and thus preventing mitochondrial deposition of A beta.