Neuroinflammation involving peripheral immune cells, particularly T lymphocytes, has been implicated in Alzheimer's disease (AD) progression. Metabolic dysregulation in sphingolipid pathways may influence neuroinflammatory processes in AD pathogenesis. However, the specific roles of T cell subsets and their interactions with metabolic pathways in AD pathogenesis remain unclear. To determine the causal contributions of peripheral T cell subsets to AD risk and investigate whether blood metabolites mediate this association. We integrated single-cell RNA sequencing with flow cytometry to identify dynamic alterations in T cell subsets during AD progression. Adoptive transfer experiments in APP/PS1 mice validated the functional roles of specific T cell populations. Two-sample Mendelian randomization (MR) evaluated causal relationships between T cell traits and AD risk, while two-step MR assessed the mediating role of blood metabolites. CD4 effector memory (EM) and CD8 central memory (CM) T cells expanded in AD patients, particularly during mild cognitive impairment. Adoptive transfer of either CD4 EM or CD8 CM T cells into APP/PS1 mice exacerbated cognitive deficits and amyloid-β pathology. MR revealed causal associations of CM CD8br % T cell (OR = 1.22, 95 % CI: 1.07-1.39, P = 0.002) and EM CD4+ % CD4+ (OR = 1.09, 95 % CI: 1.01-1.18, P = 0.027) with AD risk. Elevated plasma ceramide levels were also causally associated with increased AD risk (OR = 1.34, 95 % CI: 1.10-1.64, P = 0.004), with CD4 EM influencing ceramide levels (OR = 1.03, 95 % CI: 1.01-1.06, P = 0.020). Ceramide mediated 11.20 % of the effect between CD4 EM and AD pathogenesis. This study identifies CD4 EM and CD8 CM T cells as key drivers of AD-related neuroinflammation and uncovers a possible immunometabolic pathway linking CD4 EM, ceramide metabolism, and AD risk, suggesting potential targets for early diagnosis and therapeutic intervention.

Background: Gut dysbiosis is implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH) caused by diets rich in advanced glycation end products (AGEs). European bilberry extract (EBE) exerts a regulatory effect on gut microbiota. Nevertheless, it is still unknown whether EBE influences NASH via gut microbiota and their metabolites. This study aimed to investigate the effects and underlying mechanisms of EBE on NASH caused by a long-term AGEs diet. Methods: Rats fed with a high-AGE diet were orally administered with EBE for 80 weeks, and NASH was measured. 16S rRNA analysis and targeted metabolomics were used to detect gut microbiota and SCFA, respectively. The hepatic expression of SCFA receptors and that of the HMGB1/RAGE/NF-κB signaling pathway were detected to investigate the possible molecular mechanism. Results: EBE reduced the accumulation of AGEs in the circulation and liver of high-AGE diet-fed rats. EBE also ameliorated impaired glucose tolerance and insulin sensitivity, liver inflammation, steatosis, fibrosis, and dysfunction in high-AGE-fed rats. EBE reshaped high-AGE diet-induced gut dysbiosis by increasing short-chain fatty acid (SCFA)-producing bacteria and SCFA levels and reducing deleterious bacteria. Mechanistically, EBE promoted the activation of GPR43 and inhibited the activation of downstream HDAC3 and HMGB1/RAGE/NF-κB signaling pathway in the liver of high-AGE diet-fed rats. Additionally, EBE decreased the levels of TNF-α, IL-1β, and IL-6 and increased the level of IL-10 in the liver of high-AGE diet-fed rats. Conclusions: EBE promoted the production of SCFA, which might engage with the GPR43 receptor and inhibited the activation of HDAC3 and HMGB1/RAGE/NF-κB signaling pathway, ultimately alleviating NASH caused by a high-AGE diet.

Background/Objectives: Skin aging is accompanied by increased protein glycation in the skin, suggesting a potential link between dietary advanced glycation end products (AGEs) and skin aging. European bilberry extract (EBE), rich in anthocyanins, has shown potential in reducing AGEs; however, its protective effects against AGE-induced skin aging and the underlying mechanisms remain unclear. We aimed to investigate the association between roasted high-AGE diet exposure and skin aging, and to evaluate the protective effects of EBE and its potential mechanisms. Methods: A long-term roasted high-AGE diet exposure model was established in rats using a roasted high-AGE diet. Rats received EBE (100 mg/kg/day) or vehicle by oral gavage for 16 months. AGE levels were quantified by UHPLC-MS/MS. Skin aging phenotypes were assessed by histomorphometry and senescence-related biomarkers. Lipidomics analysis was performed to evaluate alterations in skin lipid profiles and the effects of EBE. Results: In rats, high-AGE feeding increased circulating and skin-deposited AGEs, reduced epidermal and stratum corneum thickness, and elevated senescence markers. Lipidomics revealed significant lipid remodeling, including decreased unsaturated fatty acids and glycerolipids; these lipid alterations were consistent with changes in lipid pathways related to barrier integrity, energy storage, and inflammatory signaling. EBE supplementation reduced systemic and cutaneous AGE accumulation, improved skin structure, attenuated senescence, and partially restored lipid homeostasis, including lipids associated with barrier function, energy storage, and inflammation. Conclusions: A roasted high-AGE diet is associated with and may accelerate skin aging, accompanied by lipid metabolism disruption and activation of inflammation-related pathways. EBE alleviates roasted high-AGE diet-induced skin aging and barrier-related molecule disruption, along with restoring lipid homeostasis and suppressing pro-inflammatory responses.