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Brain lipid profiles and oligodendrocyte gene expression show discordant responses to high-fat diet in Alzheimer’s disease mice.

ABSTRACT: The brain is a lipid-rich organ, with myelin sheaths containing exceptionally high levels of lipids. Oligodendrocyte dysfunction and myelin lipid deregulation have been implicated in Alzheimer’s disease (AD), yet their precise roles remain unclear. In this study, we examined lipid metabolic alterations, with focus on primary myelin lipids, in AppNL-G-F/NL-G-F (App) AD model mice fed either a normal control diet (NCD) or a high-fat diet (HFD). Brain lipid profiles were altered in App mice, with differential effects depending on diet. Notably, oligodendrocyte gene expression patterns, including those involved in myelin lipid metabolic pathways, were similar between NCD- and HFD-fed App mice and did not correspond with the observed changes in brain lipid composition. This discrepancy indicates that myelin lipid homeostasis in the AD brain is regulated by mechanisms beyond transcriptional control, likely involving post-translational regulation, inter-glial metabolic interactions, and brain-periphery lipid exchange. Importantly, HFD intake did not exacerbate cognitive impairment or neuroinflammation in App mice; rather, HFD-fed App mice showed improved learning during behavioral testing and reduced astrocytic activation. These findings suggest that dietary fat intake does not worsen—and may partially ameliorate—certain aspect of AD pathology, highlighting the complex and context-dependent relationship between metabolic interventions and neurodegenerative disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE304308 | GEO | 2026/01/25

REPOSITORIES: GEO

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Project description:Obesity and diabetes associated visual impairment and vascular dysfunctions are increasing reasons for vision loss. The detailed mechanisms in these diseases are still largely unknown, but mice models have been useful to study these mechanisms and explore the detailed effects of potential compounds. Such compounds usually have antioxidant and anti-inflammatory properties. These properties are found in anthocyanins and a major source of dietary anthocyanins in Nordic diet is bilberries (European wild blueberries, Vaccinium myrtillus). In this explorative study we show results with differentially expressed genes in retina using a high-fat diet (HFD) mouse model. Our findings displayed differential regulation of genes in pathways for apoptosis, inflammation and oxidative stress, especially systemic lupus erythematosus (SLE), mitogen activated protein kinase (MAPK) and glutathione metabolism. Mice fed with HFD had increased retinal gene expression of several crystallins, which was reduced in the retina of mice fed with bilberries. Bilberries seem to reduce the expression of genes in MAPK and to increase the expression of genes in glutathione metabolism pathway. All together despite minor effects in the mouse phenotype, a diet rich in bilberries may prevent the retinal gene expression changes in the early stages of obesity. Mice were fed ad libitum with normal control diet (NCD, 10% kcal fat), high-fat diet (HFD, 45% kcal fat), 5% (w/w) freeze-dried biberries (Vaccinium myrtillus) in NCD (NCD+BB) or HFD (HFD+BB) for 12 weeks. Diets were prepared in Research Diets Inc. Feed consumption and weight gain were measured during the feeding trial, and blood pressure and serum markers of obesity at the end. Retinas were collected and RNA extracted from all 24 mice samples, and pooled retinas from 4 mice per group were hybridized with standard Illumina protocols. The expression in retinas was analyzed using R, Pathvisio and DAVID to screen for differences between high-fat and berry induced changes to control diets and further bilberry induced changes to HFD up- or downregulated transcripts. diet: NCD, HFD, NCD+BB, HFD+BB

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Brain lipid profiles and oligodendrocyte gene expression show discordant responses to high-fat diet in Alzheimer’s disease mice.

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