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.

Acrylamide (ACR) is a commonly used organic compound that exhibits evident neurotoxicity in humans. Our previous studies showed that the mechanisms of ACR-caused neurotoxicity included apoptosis, PERK-mediated endoplasmic reticulum stress, and autophagy, but the relationships among them were still unclear. This paper investigated the relationships among apoptosis, autophagy, and the PERK pathway to demonstrate the mechanism of ACR neurotoxicity further. Different doses of ACR were set to value ACR toxicity. Then, a PERK inhibitor and autophagy inhibitor, GSK2606414 and 3-methyladenine (3-MA), were used separately to inhibit the PERK pathway and autophagy activation in SH-SY5Y cells under ACR treatment. With the increase of ACR dose, the apoptotic rate increased in a dose-dependent manner. After the inhibition of the PERK pathway, the activated apoptosis and autophagosome accumulation caused by ACR were alleviated. Under 3-MA and ACR treatment, the autophagy inhibition deteriorated apoptosis in SH-SY5Y cells but had no significant effect on ACR-induced PERK pathway activation; thus, PERK pathway-induced autophagy had an antiapoptotic role in this condition. This paper provides an experimental basis for exploring potential molecular targets to prevent and control ACR toxicity.

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.