Increased Electron Paramagnetic Resonance Signal Correlates with Mitochondrial Dysfunction and Oxidative Stress in an Alzheimer’s disease Mouse Brain

Article type: Research Article

Authors: Fang, Du^{a; 1} | Zhang, Zhihua^{c; a; 1} | Li, Hang^c | Yu, Qing^{a; d} | Douglas, Justin T.^b | Bratasz, Anna^e | Kuppusamy, Periannan^f | Yan, Shirley ShiDu^{a; *}

Affiliations: [a] Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA | [b] Nuclear Magnetic Resonance Laboratory, Molecular Structures Group, School of Pharmacy, University of Kansas, Lawrence, KS, USA | [c] School of Life Sciences, Beijing Normal University, Beijing, China | [d] State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du, China | [e] Small Animal Imaging Core, Ohio State University, Columbus, OH, USA | [f] Department of Radiology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA

Correspondence: [*] Correspondence to: Dr. Shirley ShiDu Yan, Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Ave., Lawrence, KS 66047, USA. Tel.: +1 785 864 3637; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. The pathological features are amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles. Many studies have suggested that oxidative damage induced by reactive oxygen species (ROS) is an important mechanism for AD progression. Our recent study demonstrated that oxidative stress could further impair mitochondrial function. In the present study, we adopted a transgenic mouse model of AD (mAPP, overexpressing AβPP/Aβ in neurons) and performed redox measurements using in vivo electron paramagnetic resonance (EPR) imaging with methoxycarbamyl-proxyl (MCP) as a redox-sensitive probe for studying oxidative stress in an early stage of pathology in a transgenic AD mouse model. Through assessing oxidative stress, mitochondrial function and cognitive behaviors of mAPP mice at the age of 8-9 months, we found that oxidative stress and mitochondrial dysfunction appeared in the early onset of AD. Increased ROS levels were associated with defects of mitochondrial and cognitive dysfunction. Notably, the in vivo EPR method offers a unique way of assessing tissue oxidative stress in living animals under noninvasive conditions, and thus holds a potential for early diagnosis and monitoring the progression of AD.

Keywords: Aβ accumulation, cognitive function, mitochondrial dysfunction, oxidative stress

DOI: 10.3233/JAD-150917

Journal: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 571-580, 2016