Biology subjects

Plafker, K. S.

Publications and source records attributed to Plafker, K. S..

3 recordsLinked to original sources

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↗

bioRxiv2026

Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration

Amyloid Precursor Protein (APP) has been reported to partially localize to mitochondria, and mitochondrial dysfunction is a key feature of Alzheimers disease; however, the mechanisms linking APP to mitochondrial functions remain incompletely defined. In this study, we identified an interaction between APP and phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein phosphatase. We confirmed their endogenous interaction in mouse brain tissue and determined that APP and PGAM5 are both present at mitochondria-ER contact sites (MERCS) and. Using in vitro binding assays, we demonstrate a direct interaction between the linker region of APP and a region of PGAM5 that includes the Kelch-like ECH-associated protein 1 (Keap-1) binding domain. PGAM5 is known to anchor a portion of Nuclear factor erythroid 2 p45-related factor 2 (Nrf2) through Keap1 at the outer mitochondrial membrane and regulates mitochondrial respiration and stress responses. We found that the Nrf2-regulated genes Hmox1 (Heme oxygenase-1) and Nqo1 (NADH:quinone oxidoreductase 1), which are involved in mitochondrial respiration, are downregulated in APP KO astrocytes. Accordingly, mitochondria isolated from the brains of APP knockout (KO) mice have impaired substrate-specific respiration and electron transport chain (ETC) function. Together, these findings suggest that APP supports mitochondrial respiration by binding to PGAM5 and modulating Keap1-Nrf2 signaling.

neuroscience↗

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↗