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bioRxiv · 10.1101/2022.04.05.487092

ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer's disease pathology in APP/PS1 mice.

Hsieh, C.-J.·Hou, C.·Zhu, Y.·Lee, J. Y.·Kohli, N.·Gallagher, E.·Xu, K.·Lee, H.·Li, S.·McManus, M. J.·Mach, R. H.
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Abstract

PurposeOxidative stress is implicated in the pathogenesis of the most common neurodegenerative diseases, such as Alzheimers disease (AD). However, tracking oxidative stress in the brain has proven difficult and impeded its use as a biomarker. Herein, we investigate the utility of a novel positron emission tomography (PET) tracer, [18F]ROStrace, as a biomarker of oxidative stress throughout the course of AD in the well-established APP/PS1 double mutant mouse model. MethodsPET imaging studies were conducted in wild-type (WT) and APP/PS1 mice at 3 different time points, representing early (5 mo.), middle (10 mo.), and advanced (16 mo.) life (n = 6-12, per sex). Semi-quantitation SUVRs of the plateau phase (40-60min post-injection; SUVR40-60) of ten brain subregions were designated by the Mirrione atlas and analyzed by Pmod. Statistical parametric mapping (SPM) was used to distinguish brain regions with elevated ROS in APP/PS1 relative to WT in both sexes. The PET studies were validated by ex vivo autoradiography and immunofluorescence with the parent compound, dihydroethidium. Results[18F]ROStrace retention was increased in the APP/PS1 brain compared to age-matched controls by 10 mo. of age (p < 0.0001), and preceded the accumulation of oxidative damage in APP/PS1 neurons at 16mo. (p < 0.005). [18F]ROStrace retention and oxidative damages were higher and occurred earlier in female APP/PS1 mice as measured by PET (p < 0.001), autoradiography and immunohistochemistry (p < 0.05). [18F]ROStrace differences emerged mid-life, temporally and spatially correlating with increased A{beta} burden (r2 = 0.36; p = 0.0003), which was also greatest in the female brain (p < 0.001). Conclusions[18F]ROStrace identifies increased oxidative stress and neuroinflammation in APP/PS1 female mice, concurrent with increased amyloid burden mid-life. Differences in oxidative stress during this crucial time may partially explain the sexual dimorphism in AD. [18F]ROStrace may provide a long-awaited tool to stratify at-risk patients who may benefit from antioxidant therapy prior to irreparable neurodegeneration.

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Hsieh, C.-J., Hou, C., Zhu, Y., Lee, J. Y., Kohli, N., Gallagher, E., Xu, K., Lee, H., Li, S., McManus, M. J., Mach, R. H.. 2022-04-08. ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer's disease pathology in APP/PS1 mice.. https://doi.org/10.1101/2022.04.05.487092

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