Ergothioneine improves Aβ clearance in the neuroretina of a mouse model of Alzheimer’s disease (AD).

Abstract

Purpose : Ergothioneine (Ergo) is a naturally occurring dietary antioxidant. Its uptake is dependent on the transporter, organic cation transporter novel-type 1 (OCTN1). OCTN1 is highly expressed in blood cells, and ocular and brain tissues that are likely predisposed to oxidative stress. Ergo may protect the brain and eye against oxidative damage and neuroinflammation, however underlying mechanism remains unclear. Amyloid-beta (Aβ) clearance is a complex process mediated by various systems and cell types. Impaired Aβ clearance may jeopardize Alzheimer’s disease (AD). Since the retina is an extension of CNS, here we investigated Aβ load along with glial cell markers in the neuroretinas of Ergo-treated vs. non-treated AD transgenic mice and C57BL/6J (WT) controls.

Methods : Three age-matched groups (Ergo-treated 5xFAD, non-treated 5xFAD and 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). Pixel count data were analysed with Kruskal-Wallis H test followed by Dunn’s post-hoc test with Bonferroni adjusted significance level of p <0.05 for multiple comparisons.

Results : OCTN1 expression was significantly low in the eye cross-sections of 5xFAD mice vs. WT controls. Strong Aβ labeling, detected in the superficial ILM/NFL layers in wholemounts of Ergo-treated 5xFAD and WT controls vs. non-treated 5xFAD reflects the existence of an effective Aβ clearance system. This was supported by imaging of cross-sections where Aβ labeling was significantly low in the neuroretina (GCL, INL, etc.) in Ergo-treated 5xFAD vs. non-treated 5xFAD. Moreover, semi-quantitative analysis in wholemounts identified a significantly reduced number of large Aβ deposits, and a significantly increased number of IBA1(+)ve blood-derived phagosomes in Ergo-treated 5xFAD vs. non-treated 5xFAD. GFAP and IBA1 labeling were significantly higher in wholemounts of WT controls vs. non-treated 5xFAD, whereas it was nonsignificant between WT controls vs. Ergo-treated 5xFAD. In eye cross-sections, IBA1 labeling was comparable whereas, GFAP labeling was significantly different across the 3 groups.

Conclusions : Enhanced Aβ clearance in Ergo-treated 5xFAD suggests that Ergo uptake may promote Aβ clearance possibly by blood-derived phagocytes and the perivascular or glymphatic system.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.