Improved synthesis of an ergothioneine PET radioligand for imaging oxidative stress in Alzheimer’s disease

Behof, William J.; Whitmore, Clayton A.; Haynes, Justin R.; Rosenberg, Adam J.; Tantawy, Mohammed Noor; Peterson, Todd E.; Harrison, Fiona E.; Beelman, Robert B.; Wijesinghe, Printha; Matsubara, Joanne A.; Pham, Wellington

doi:10.1002/1873-3468.14303

Cited by 6 publications

(3 citation statements)

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“…Recently, we reported that longitudinal consumption of Ergo reduced Aβ plaques in the brain cross-sections, oxidative stress, and rescued glucose metabolism in a 5XFAD mouse model ( Whitmore et al, 2022 ). In our previous work, an efficient and reproducible preparation of [ 11 C]-labeled Ergo PET radioligand to detect threshold levels of oxidative stress in a preclinical animal model of AD was also reported ( Behof et al, 2022 ).…”

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confidence: 99%

Ergothioneine, a dietary antioxidant improves amyloid beta clearance in the neuroretina of a mouse model of Alzheimer’s disease

et al. 2023

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IntroductionErgothioneine (Ergo) is a naturally occurring dietary antioxidant. Ergo uptake is dependent on the transporter, organic cation transporter novel-type 1 (OCTN1) distribution. OCTN1 is highly expressed in blood cells (myeloid lineage cells), brain and ocular tissues that are likely predisposed to oxidative stress. Ergo may protect the brain and eye against oxidative damage and inflammation, however, the underlying mechanism remains unclear. Amyloid beta (Aβ) clearance is a complex process mediated by various systems and cell types including vascular transport across the blood–brain barrier, glymphatic drainage, and engulfment and degradation by resident microglia and infiltrating innate immune cells. Impaired Aβ clearance is a major cause for Alzheimer’s disease (AD). Here we investigated neuroretinas to explore the neuroprotective effect of Ergo in a transgenic AD mouse model.MethodsAge-matched groups of Ergo-treated 5XFAD, non-treated 5XFAD, and C57BL/6J wildtype (WT controls) were used to assess Ergo transporter OCTN1 expression and Aβ load along with microglia/macrophage (IBA1) and astrocyte (GFAP) markers in wholemount neuroretinas (n = 26) and eye cross-sections (n = 18). Immunoreactivity was quantified by fluorescence or by semi-quantitative assessments.Results and discussionOCTN1 immunoreactivity was significantly low in the eye cross-sections of Ergo-treated and non-treated 5XFAD vs. WT controls. Strong Aβ labeling, detected in the superficial layers in the wholemounts of Ergo-treated 5XFAD vs. non-treated 5XFAD reflects the existence of an effective Aβ clearance system. This was supported by imaging of cross-sections where Aβ immunoreactivity was significantly low in the neuroretina of Ergo-treated 5XFAD vs. non-treated 5XFAD. Moreover, semi-quantitative analysis in wholemounts identified a significantly reduced number of large Aβ deposits or plaques, and a significantly increased number of IBA1(+)ve blood-derived phagocytic macrophages in Ergo-treated 5XFAD vs. non-treated 5XFAD. In sum, enhanced Aβ clearance in Ergo-treated 5XFAD suggests that Ergo uptake may promote Aβ clearance possibly by blood-derived phagocytic macrophages and via perivascular drainage.

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Section: Discussionmentioning

confidence: 99%

Ergothioneine, a dietary antioxidant improves amyloid beta clearance in the neuroretina of a mouse model of Alzheimer’s disease

et al. 2023

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“…(Supplementary Data on the analysis methods, Figure S3). Recently, our [ 11 C]ERGO PET radioligand has been demonstrated as an imaging biomarker for oxidative stress in a mouse model of lipopolysaccharides (LPS) [32] and 5XFAD mice [38]. Thus, in this study, [ 11 C]ERGO PET radioligand was used to assess the fluctuation in oxidative stress with respect to the ERGO therapy.…”

Section: Longitudinal Consumption Of Ergo Mitigates Aβ Aggregation In...mentioning

confidence: 99%

Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer’s Disease

et al. 2022

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Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood–brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer’s disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [11C]PIB, [11C]ERGO, and [18F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy.

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“…Perhaps, however, deficiency diseases are staring us in the face: low blood or plasma levels of ET are correlated with increased risk of frailty [16][17][18], cardiovascular disease [19], mild cognitive impairment [18,[20][21][22], dementia [22,23] and Parkinson's disease [24]. Indeed, ET has many neuroprotective properties [4,5,18,26,27], as reviewed in detail in this special issue [18,25,26]. Consistent with a key protective role of ET against the development of age-related diseases, higher dietary consumption of mushrooms, a rich source of ET [9], is associated with lower disease risk [28][29][30][31].…”

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confidence: 99%

Ergothioneine, where are we now?

Halliwell

Cheah

2022

FEBS Letters

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Improved synthesis of an ergothioneine PET radioligand for imaging oxidative stress in Alzheimer’s disease

Cited by 6 publications

References 43 publications

Ergothioneine, a dietary antioxidant improves amyloid beta clearance in the neuroretina of a mouse model of Alzheimer’s disease

Ergothioneine, a dietary antioxidant improves amyloid beta clearance in the neuroretina of a mouse model of Alzheimer’s disease

Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer’s Disease

Ergothioneine, where are we now?

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