Biology subjects

Walton, D. A.

Publications and source records attributed to Walton, D. A..

3 recordsLinked to original sources

bioRxiv2026

Functional and molecular profiles of the neuroretina and retinal pigmented epithelium-choroid in response to aging and Nrf2 deletion

Purpose: Age is the leading factor for age-related macular degeneration (AMD), in which retinal pigmented epithelium (RPE) atrophy is a hallmark. The nuclear factor-erythroid 2-related factor 2 (Nrf2), a major anti-stress transcription factor, decreases in AMD, suggesting bioenergetic stress interacts with age during AMD pathogenesis. We profiled visual function and gene expression of the retina and RPE-choroid with Nrf2 deletion and aging. Methods: We tested 3mo and 14mo Nrf2 null (Nrf2 KO) and Nrf2 WT mice for optokinetic tracking (OKT) and dark-adapted electroretinography (ERG) responses. Eyes were harvested for retina outer nuclear layer (ONL) thickness analysis and retina and RPE-choroid cup RNA isolation for RNAseq profiling. Results: Visual acuity was reduced with aging with lower values in the Nrf2 KO vs Nrf2 WT comparison at 14mo. We observed aged-related reduction of a-, b-, and c-wave ERG amplitudes in both WT and KO mice. Age-related c-wave decline was exacerbated by Nrf2 loss. By RNAseq, two-way ANOVA of RPE-choroid samples revealed differentially expressed genes (DEGs) with age and genotype main effects, as well as DEGs with age and genotype interaction effects. Age DEGs were over-represented in pathways related to inflammation and phagocytosis. Genotype DEGs were associated with alterations in antioxidant and inflammatory processes. Retina RNAseq showed age and genotype DEGs. Conclusions: Ablation of Nrf2 exacerbates age-related declines suggesting that decrease in Nrf2 with aging has functional consequences for inflammation/resiliency. We provide retina and RPE-choroid bulk-RNAseq datasets from the same cohort of mice that can be interrogated to better understand degeneration of retina/RPE-choroid.

molecular biology↗

bioRxiv2026

A KETOGENIC DIET PROMOTES BLOOD-SPINAL CORD BARRIER RESEALING AND PHENOTYPIC SWITCHING OF PRO-INFLAMMATORY MYELOID CELL INFILTRATES IN A PRECLINICAL MODEL OF MULTIPLE SCLEROSIS.

We previously reported that a medium chain triglyceride and{omega} -3 fatty acid enriched ketogenic diet (KD) restored vision and motor functions to mice undergoing experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis (MS). In the mechanistic studies reported here we show that the KD dramatically reduces the infiltration of CD45HI immune cells into the spinal cords of EAE mice when initiated at symptom onset and fed for 2 weeks. Two mechanisms contributed to this reduced accumulation of infiltrates. First, the KD accelerated resealing of the blood-SC barrier (BSCB) in both sexes. This resealing accompanied motor score functional recovery and occurred whether KD feeding was initiated the day of symptom onset or 1 week after symptom onset. Consistent with this resealing, the KD reduced SC levels of soluble IL-1{beta}, a primary cytokine associated with compromising the integrity of CNS-blood barriers. A second mechanism was that the KD increased the percentage of spinal cord infiltrates undergoing apoptosis. Beyond reducing the total abundances of immune cell infiltrates by these two mechanisms, the KD also preserved subpopulations of neutrophils and non-classical mono/macs expressing surface markers associated with inflammation resolution, healing, and tissue repair. Studies leveraging global knockout mouse strains showed unexpectedly that the efficacy of the KD in this interventional paradigm was independent of both the hydroxycarboxylic acid receptor 2 (HCA2) and the anti-stress transcription factor, Nrf2. Collectively, this work advances novel insights by which a KD ameliorates autoimmune-mediated MS-like pathologies to promote functional recovery and more broadly, implies that this dietary strategy has potential benefit for facilitating the healing of disrupted blood-CNS barriers and resolving inflammation in multiple neurodegenerative diseases.

immunology↗

bioRxiv2022

DIETARY PROTECTION AGAINST THE VISUAL AND MOTOR DEFICITS INDUCED BY EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

Five to eight percent of the world population currently suffers from at least one autoimmune disorder. Despite multiple immune modulatory therapies for autoimmune demyelinating diseases of the central nervous system, these treatments can be limiting for subsets of patients due to adverse effects and expense. To circumvent these barriers, we investigated a nutritional intervention in mice undergoing experimental autoimmune encephalomyelitis (EAE). This model of autoimmune-mediated demyelination induces visual and motor pathologies similar to those experienced by people with multiple sclerosis (MS). Here, we report that limiting dietary carbohydrates by feeding mice a ketogenic diet (KD) enriched in medium chain triglycerides, -linolenic acid, and fiber is effective at mitigating EAE-induced optic neuritis and motor deficits. The KD was efficacious when fed as a preventive regimen prior to EAE immunization as well as when initiated as an interventional regimen following the onset of EAE symptoms. The KD minimally impacted body weight during the experimental time course, increased circulating ketones, prevented motor and ocular deficits, preserved myelination of the optic nerve, and reduced infiltration of immune cells to optic nerves. The KD also increased anti-inflammatory-associated omega-3 fatty acids in the plasma and reduced select cytokines in the circulation associated with EAE-mediated pathological inflammation. In light of ongoing clinical trials using dietary strategies to treat people with MS, these findings support that a KD promotes a systemic anti-inflammatory milieu and ameliorates autoimmune-induced demyelinating visual and motor deficits.

immunology↗