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Mitochondria-Targeting Ceria Nanoparticles as Antioxidants for Alzheimer’s Disease Hyek Jin Kwon, Moon-Yong Cha, Dokyoon Kim, Dong Kyu Kim, Min Soh, Kwangsoo Shin, Taeghwan Hyeon, and Inhee Mook-Jung ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.5b08045 • Publication Date (Web): 04 Feb 2016 Downloaded from http://pubs.acs.org on February 9, 2016
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Mitochondria-Targeting Ceria Nanoparticles as Antioxidants for Alzheimer’s Disease Hyek Jin Kwon, †,‡,⊥ Moon-Yong Cha,§,⊥ Dokyoon Kim,† Dong Kyu Kim,§ Min Soh,†,‡ Kwangsoo Shin,†,‡ Taeghwan Hyeon,*,†,‡ Inhee Mook-Jung*,§ †
Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 151-742, Republic of
Korea, ‡School of Chemical and Biological Engineering and Institute of Chemical Processes, Seoul National University, Seoul 151-742, Republic of Korea, §Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-744, Republic of Korea. ⊥
These authors contributed equally to this work.
* Address correspondence to
[email protected],
[email protected].
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Abstract Mitochondrial oxidative stress is a key pathologic factor in neurodegenerative diseases, including Alzheimer’s disease. Abnormal generation of reactive oxygen species, resulting from mitochondrial dysfunction, can lead to neuronal cell death. Ceria (CeO2) nanoparticles are known to function as strong and recyclable ROS scavengers by shuttling between Ce3+ and Ce4+ oxidation states. Consequently, targeting ceria nanoparticles selectively to mitochondria might be a promising therapeutic approach for neurodegenerative diseases. Here, we report the design and synthesis of triphenylphosphonium-conjugated ceria nanoparticles that localize to mitochondria and suppress neuronal death in 5XFAD transgenic Alzheimer’s disease mouse model. The triphenylphosphonium-conjugated
ceria
nanoparticles
mitigate
reactive
gliosis
and
morphological mitochondria damage observed in these mice. Altogether, our data indicate that the triphenylphosphonium-conjugated ceria nanoparticles are a potential therapeutic candidate for mitochondrial oxidative stress in Alzheimer’s disease.
KEYWORDS: Alzheimer’s disease • ceria nanoparticles • mitochondria • reactive oxygen species • therapeutic agents
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Alzheimer’s disease (AD) is one of the most common types of dementia and affects approximately 10% of people aged 65 years or more. The major pathological indicators of AD comprise the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in brain.1,2 Although numerous studies imply the presence of crosstalk between Aβ and various molecular signaling pathways, the exact mechanism how Aβ potentiates AD pathogenesis has not been fully elucidated yet.3-6 Additionally, Aβ-induced mitochondrial dysfunction also has been known to be a possible cause of AD through abnormal production of reactive oxygen species (ROS), such as superoxide anion, hydroxyl radical, and hydrogen peroxide.7,8 Mitochondria are elongated membrane organelles that are found in the cytoplasm of cells and have a diameter and a height of 0.5-1 µm and 1-10 µm, respectively. Mitochondria supply cells with adenosine triphosphate (ATP) through oxidative phosphorylation process to maintain cellular energy homeostasis. ROS byproducts generated during this process can cause mitochondrial dysfunctions, such as DNA mutation and promotion of intrinsic apoptosis pathways.9-11 Although the molecular basis of the impaired mitochondrial functions in AD is still far from being comprehended, several previous studies revealed that the production of ROS is involved with the interactions of Aβ peptides in mitochondria with resident proteins, such as cyclophilin D, alcohol dehydrogenase, and ATP synthase.12-14 Since this kind of ROS-induced mitochondrial dysfunctions precedes the Aβ plaque build-up in brain, the hallmark of AD,15,16 therapeutic agents that can protect mitochondria against oxidative stress from ROS would be very useful for the prevention and early-stage treatment of AD. For example, some mitochondria-specific antioxidants, including MitoQ and SS31, are known to work effectively against AD-related oxidative stress and synaptic dysfunctions.17-19
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Ceria (CeO2) nanoparticles less than 5 nm are known to exhibit ROS scavenging activity in a recyclable way by reversible binding of oxygen atoms and shuttling between the Ce3+ (reduced) and Ce4+ (oxidized) states on their surface.20-22 They have been successfully applied to protect cells against superoxide and hydrogen peroxide, which are two predominant forms of ROS, using their superoxide dismutase-mimetic and catalase-mimetic activities, respectively.20-22 Various therapeutic potentials of the ceria nanoparticles also have been demonstrated for neuroand cardio-protection, wound healing, and treatment of chronic inflammation, cancer, and ocular disorders.23-27 In particular, small ceria nanoparticles (
