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

Abstract

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.

MicroRNAs in tear fluids predict underlying molecular changes associated with Alzheimer’s disease

“…Ergothioneine is a naturally occurring dietary antioxidant and its uptake and accumulation are purely dependent on OCTN1 distribution. Beneficial effects of ergothioneine uptake against Aβ accumulations have been reported in our previous studies (Whitmore et al, 2022;Wijesinghe et al, 2023). We also reported significantly depleted OCTN1 transporters in the whole eye of transgenic 5XFAD mice by comparing it with age-matched C57BL/6J WT controls (Wijesinghe et al, 2023).…”

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

“…Neuroprotective capabilities of Ergo have been demonstrated in a range of in vitro and in vivo studies, however underlying mechanism remains unclear. 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 ).…”

Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST

“…Interestingly, EGT levels in human plasma decrease with advanced age and low levels of EGT in human plasma are associated with a range of age-related disorders 18,22 . Conversely, EGT supplementation shows promising results in animal models mimicking a broad spectrum of human diseases including Alzheimer’s disease and depression and during aging in mice 22,26,50,51 .…”