Dataset Information

[¹⁸F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer's disease pathology in APP/PS1 mice.

ABSTRACT:

Background

Oxidative stress is implicated in the pathogenesis of the most common neurodegenerative diseases, such as Alzheimer's 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. PET 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 (40-60 min post-injection; SUVR_40-60) 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 16 mo. (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 midlife, temporally and spatially correlating with increased Aβ 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 midlife. 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.

SUBMITTER: Hsieh CJ

PROVIDER: S-EPMC9329498 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionAlzheimer's disease (AD) is the most common form of dementia worldwide. The biological mechanisms underlying the pathogenesis of AD aren't completely clear. Studies have shown that the gut microbiota could be associated with AD pathogenesis; however, the pathways involved still need to be investigated.AimsTo explore the possible pathways of the involvement of gut microbiota in AD pathogenesis through metabolites and to identify new AD biomarkers.MethodsSeven-month-old APP/PS1 mice were used as AD models. The Morris water maze test was used to examine learning and memory ability. 16S rRNA gene sequencing and widely targeted metabolomics were used to identify the gut microbiota composition and fecal metabolic profile, respectively, followed by a combined analysis of microbiomics and metabolomics.ResultsImpaired learning abilities were observed in APP/PS1 mice. Statistically significant changes in the gut microbiota were detected, including a reduction in β-diversity, a higher ratio of Firmicutes/Bacteroidota, and multiple differential bacteria. Statistically significant changes in fecal metabolism were also detected, with 40 differential fecal metabolites and perturbations in the pyrimidine metabolism. Approximately 40% of the differential fecal metabolites were markedly associated with the gut microbiota, and the top two bacteria associated with the most differential metabolites were Bacillus firmus and Rikenella. Deoxycytidine, which causes changes in the pyrimidine metabolic pathway, was significantly correlated with Clostridium sp. Culture-27.ConclusionsGut microbiota may be involved in the pathological processes associated with cognitive impairment in AD by dysregulating pyrimidine metabolism. B. firmus, Rikenella, Clostridium sp. Culture-27, and deoxyuridine may be important biological markers for AD. Our findings provide new insights into the host-microbe crosstalk in AD pathology and contribute to the discovery of diagnostic markers and therapeutic targets for AD.

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[¹⁸F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer's disease pathology in APP/PS1 mice.

Background

Results

Conclusions

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[18F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer's disease pathology in APP/PS1 mice.

Background

Results

Conclusions

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OmicsDI is part of the ELIXIR infrastructure

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[¹⁸F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer's disease pathology in APP/PS1 mice.