Abstract
Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid β (Aβ) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral Aβ levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known Aβ-cleaving protease, on oligomeric Aβ-induced cell death were evaluated. NIa cleaved monomeric and oligomeric Aβ at a similar rate, whereas NEP only cleaved monomeric Aβ. Oligomeric Aβ-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled Aβ 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 Aβ and thus preventing mitochondrial deposition of Aβ.
Highlights
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder that is characterized by progressive memory impairment and cognitive dysfunction
The hallmarks of AD are the formation of intracellular neurofibrillary tangles composed of hyper-phosphorylated tau and extracellular amyloid plaques mainly composed of amyloid b (Ab)
We further showed that lentivirus-mediated expression of Nuclear inclusion a (NIa) in the brain of AD mice significantly reduced Ab pathology and improved behavioral deficits [23,24]
Summary
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder that is characterized by progressive memory impairment and cognitive dysfunction. Ab exists as soluble monomers and oligomers, and insoluble fibrils. Which of these forms of Ab is the active species that are responsible for synaptic loss and neurodegeneration in AD is controversial [3,4]. Neither monomeric nor fibrillar forms of Ab appear to be responsible [4,5]. A number of studies indicate that oligomeric Ab is the most potent neurotoxic species in association with AD [6,7,8,9,10]. Oligomeric Ab reduces neuronal viability approximately 10-fold more efficiently than fibrillar Ab [11]
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