Biology subjects

Mayhue, M.

Publications and source records attributed to Mayhue, M..

4 recordsLinked to original sources

bioRxiv2025

In vivo inhibition of stearoyl-CoA desaturase modulates the hippocampal fatty acid profile and restores density of dendritic spines in the aggressive 5xFAD model of Alzheimer s disease

While alterations in brain lipids are a central feature of Alzheimers disease (AD), therapeutic strategies targeting brain lipid metabolism are still lacking. Prior preclinical work has shown that pharmacological inhibition of the fatty acid desaturase, stearoyl-CoA desaturase (SCD), leads to recovery of hippocampal synapses with associated improvements in learning and memory in the slow-progressing 3xTg AD mouse model. Here, we used the rapidly progressing, highly amyloidogenic 5xFAD AD model to further delve into the effect of the SCD inhibitor (SCDi) on AD-associated fatty acid alterations and synapse loss. Hippocampus, cortex and plasma samples were collected from male and female 5xFAD and non-carrier control mice for fatty acid profiling and assessment of disease hallmarks. Plaque pathology, gliosis, and fatty acid alterations that included an increase in the C16:1/C16:0 desaturation index, a measure of SCD enzymatic activity, were apparent in the female hippocampus at 5 months of age, with similar fatty acid changes appearing in males by 8 months. Intracerebroventricular infusion of SCDi via osmotic pump for 28 days in 5 months old female 5xFAD and NC mice modulated the SCD-related fatty acid disturbances as well as PUFA concentrations. Quantification of Golgi staining revealed an SCDi-induced recovery of dendritic spine density. The beneficial effects of SCDi treatment on fatty acid balance and hippocampal dendritic spines in this more aggressive amyloidogenic 5xFAD model further support SCD inhibition as a promising therapeutic avenue for AD.

neuroscience↗

bioRxiv2025

Ketogenic interventions prevent alterations of the gut microbiome in transgenic Alzheimer Disease mice

Alterations in the gut microbiome constitute a feature of aging and therefore represent a therapeutic target for aging-related diseases. In this study, we investigated the impact of ketogenic interventions on the microbiome of mice genetically predisposed to Alzheimers disease (AD). AD mice exhibited several microbial alterations, notably increased levels of Bifidobacterium and decreased levels of Bacteroidetes. Ketogenic interventions, either a medium-chain triglyceride-enriched diet (MCT) or carbohydrate-free high-fat diet (CFHF), administered for 1 month restored the levels of more than 50% of the bacteria altered in AD mice, including a strong reduction in Bifidobacterium levels. Ketogenic interventions induced a shift in the gut microbiome associated with increased levels of short-chain fatty acid-producing bacteria, such as Lachnospiraceae and Muribaculaceae. MCT and CFHF also triggered diet-specific microbial changes, which may contribute to the distinct physiological effects of these diets. In conclusion, ketogenic interventions may influence AD pathophysiology by modulating the gut microbiome.

neuroscience↗

bioRxiv2024

Ketogenic interventions restore cognition and modulate peripheral metabolic dysfunctions in Alzheimer's disease mouse models

Lifestyle factors modulate dementia risk. We investigated mechanisms of dementia risk reduction by emerging dietary ketogenic interventions. We show that distinct interventions, a medium-chain triglycerides (MCT)-enriched diet and a carbohydrate-free, high-fat diet (CFHF), improve cognition and dendritic spine density of memory-associated hippocampal neurons in two mouse models of Alzheimers disease (AD). Only the CFHF diet drove increased circulating ketones, suggesting distinct underlying mechanisms. AD mice exhibited baseline and diet-induced susceptibility to peripheral metabolic disturbances that were improved by MCT and exacerbated by CFHF diets. Prominent AD-associated dysregulation of the liver transcriptome was largely restored by both interventions, but MCT also downregulated lipogenic enzymes and did not trigger a CFHF-like inflammatory signature. Novel AD- and diet-induced plasmatic changes in hormones and lipid species were identified. Thus, different ketogenic interventions yield cognitive benefits in AD models while showing intervention-specific modulation of peripheral metabolic defects, with implications for design of therapeutic ketogenic strategies.

neuroscience↗

bioRxiv2020

Cytokine priming of naive CD8+ T lymphocytes modulates chromatin accessibility that partially overlaps with changes induced by antigen simulation

BackgroundNaive CD8+ T lymphocytes undergo antigen non-specific proliferation following exposure to certain synergistic combination of inflammatory (IL-6, IL-21) and homeostatic (IL-7, IL-15) cytokines. Such cytokine-stimulated naive CD8+ T cells display increased T cell antigen receptor (TCR) sensitivity, allowing them to respond to limiting concentrations of cognate antigenic peptides and altered peptide ligands of lower affinity towards the TCR. The purpose of this study is to gain insight into the molecular mechanisms of such cytokine priming. MethodsNaive CD8+ T lymphocytes expressing the PMEL-1 transgenic TCR were stimulated with IL-15 and IL-21, and chromatin accessibility was assessed using the assay for transposase-accessible chromatin (ATAC) sequencing. Cells stimulated by the cognate antigenic peptide mgp10025-33 were used as controls. ResultsCompared to naive cells, cytokine-primed cells showed 212 opening and 484 closing peaks, whereas antigen-stimulated cells showed 12087 opening and 6982 closing peaks. However, a significant fraction of the opening (33%) and closing (63%) peaks of cytokine-primed cells overlapped with those of the antigenic stimulated cells. Chromatin accessibility peaks modulated in cytokine-primed cells were strongly represented in gene ontology pathways for T cell signaling, activation, regulation and effector functions. Many of the transcription factor binding motifs located close to the opening and closing peaks of cytokine-primed cells also occurred in antigen-stimulated cells. ConclusionsOur data suggest that by modulating the gene expression programs involved in TCR signaling, cytokine priming induces a poised state that lowers the TCR signaling threshold in naive CD8+ T cells and increases their antigen responsiveness.

immunology↗