Early detection of redox imbalance in the APPswe/PS1dE9 mouse model of Alzheimer's disease by in vivo electron paramagnetic resonance imaging

Miho C Emoto; Hideo Sato-Akaba; Naoya Hamaue; Katsuya Kawanishi; Hisashi Koshino; Shun Shimohama; Hirotada G Fujii

doi:10.1016/j.freeradbiomed.2021.05.035

Early detection of redox imbalance in the APPswe/PS1dE9 mouse model of Alzheimer's disease by in vivo electron paramagnetic resonance imaging

Free Radic Biol Med. 2021 Aug 20:172:9-18. doi: 10.1016/j.freeradbiomed.2021.05.035. Epub 2021 May 28.

Authors

Miho C Emoto¹, Hideo Sato-Akaba², Naoya Hamaue³, Katsuya Kawanishi⁴, Hisashi Koshino⁴, Shun Shimohama⁵, Hirotada G Fujii⁶

Affiliations

¹ Department of Clinical Laboratory Science, School of Medical Technology, Health Sciences University of Hokkaido, Sapporo, Hokkaido, 002-8072, Japan.
² Department of Systems Innovation, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka, 560-8531, Japan.
³ School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari, Hokkaido, 061-0293, Japan.
⁴ Department of Removable Prosthodontics, School of Dentistry, Health Sciences University of Hokkaido, Ishikari, Hokkaido, 061-0293, Japan.
⁵ Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, 060-8556, Japan.
⁶ Advanced Research Promotion Center, Health Sciences University of Hokkaido, Ishikari, Hokkaido, 061-0293, Japan. Electronic address: hgfujii@hoku-iryo-u.ac.jp.

PMID: 34058322
DOI: 10.1016/j.freeradbiomed.2021.05.035

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease that causes progressive cognitive decline. Deposition of amyloid-β (Aβ) peptides is the most important pathophysiological hallmark of AD. Oxidative stress induced by the generation of reactive oxygen species (ROS) is a prominent phenomenon in AD and is known to occur early in its course. Several reports have suggested a relationship between changes in redox status and AD pathology, including progressive Aβ deposition, glial cell activation, and inflammation. In the present study, we employed a newly designed three-dimensional continuous-wave digital electron paramagnetic resonance (EPR) imager with a blood-brain barrier (BBB)-permeable redox-sensitive piperidine nitroxide probe, 4-oxo-2,2,6,6-tetramethyl-piperidine-d₁₆-1-oxyl, for early detection of changed brain redox status. Using this system, we noninvasively compared age-matched 7-month-old AD model mice with normal littermates (WT mice). The obtained brain redox images of AD and WT mice clearly showed impaired brain redox status of AD mice compared to WT, suggesting that oxidative damage had already increased in 7-month-old AD mice compared with age-matched WT mice. The pathological changes in 7-month-old mice in this study were detected earlier than in previous studies in which only AD mice older than 9 months of age could be imaged. Since EPR images suggested that oxidative damage was already increased in 7-month-old AD mice compared to age-matched WT mice, we also evaluated antioxidant levels and the activity of superoxide dismutase (SOD) in brain tissue homogenates of 7-month-old AD and WT mice. Compared to WT mice, decreased levels of glutathione and mitochondrial SOD activity were found in AD mice, which supports the EPR imaging results indicating impaired brain redox status. These results indicate that the EPR imaging method developed in this study is useful for early noninvasive detection of altered brain redox status due to oxidative disease.

Keywords: Alzheimer's disease; Antioxidant; Brain redox status; Electron paramagnetic resonance (EPR) imaging; Oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / genetics
Amyloid beta-Peptides
Animals
Brain / diagnostic imaging
Disease Models, Animal
Electron Spin Resonance Spectroscopy
Mice
Mice, Transgenic
Neurodegenerative Diseases*
Oxidation-Reduction

Substances

Amyloid beta-Peptides