title: Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death.
abstract: Evidence indicates that nitrosative stress and mitochondrial dysfunction participate in the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Aβ) and peroxynitrite induce mitochondrial fragmentation and neuronal cell death by abnormal activation of dynamin-related protein 1 (DRP1), a large GTPase that regulates mitochondrial fission. The exact mechanisms of mitochondrial fragmentation and DRP1 overactivation in AD remain unknown; however, DRP1 serine 616 (S616) phosphorylation is likely involved. Although it is clear that nitrosative stress caused by peroxynitrite has a role in AD, effective antioxidant therapies are lacking. Cerium oxide nanoparticles, or nanoceria, switch between their Ce(3+) and Ce(4+) states and are able to scavenge superoxide anions, hydrogen peroxide and peroxynitrite. Therefore, nanoceria might protect against neurodegeneration. Here we report that nanoceria are internalized by neurons and accumulate at the mitochondrial outer membrane and plasma membrane. Furthermore, nanoceria reduce levels of reactive nitrogen species and protein tyrosine nitration in neurons exposed to peroxynitrite. Importantly, nanoceria reduce endogenous peroxynitrite and Aβ-induced mitochondrial fragmentation, DRP1 S616 hyperphosphorylation and neuronal cell death.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Dowding
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
authors.forename: W
authors.initials: W
authors.lastname: Song
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bossy
authors.affiliation: Environmental and Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
authors.forename: A
authors.initials: A
authors.lastname: Karakoti
authors.affiliation: Advanced Materials Processing and Analysis Center, Mechanical Material and Aerospace Engineering, Nanoscience and Technology Center (NSTC), University of Central Florida, Orlando, FL 32816, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.affiliation: National Center for Microscopy and Imaging Research, School of Medicine, University of California, San Diego, La Jolla, CA 92093-060, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kim
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
authors.forename: B
authors.initials: B
authors.lastname: Bossy
authors.affiliation: Advanced Materials Processing and Analysis Center, Mechanical Material and Aerospace Engineering, Nanoscience and Technology Center (NSTC), University of Central Florida, Orlando, FL 32816, USA.
authors.forename: S
authors.initials: S
authors.lastname: Seal
authors.affiliation: National Center for Microscopy and Imaging Research, School of Medicine, University of California, San Diego, La Jolla, CA 92093-060, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: National Center for Microscopy and Imaging Research, School of Medicine, University of California, San Diego, La Jolla, CA 92093-060, USA.
authors.forename: G
authors.initials: G
authors.lastname: Perkins
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
authors.forename: W T
authors.initials: WT
authors.lastname: Self
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
authors.forename: E
authors.initials: E
authors.lastname: Bossy-Wetzel
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002563:Cerium / Q000494:pharmacology*; D034281:Dynamins / Q000378:metabolism; D053768:Metal Nanoparticles; D008928:Mitochondria / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects*; D019636:Neurodegenerative Diseases / Q000517:prevention & control; D009474:Neurons / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D026361:Reactive Nitrogen Species; D030421:Peroxynitrous Acid; D002563:Cerium; C030583:ceric oxide; C519851:Dnm1l protein, rat; D034281:Dynamins