Alzheimer's disease (AD) is a neurogenerative disease and remains no effective method for stopping its progress. Ferroptosis and adaptive immunity have been proven to contribute to AD pathogenesis. Salidroside exhibits neuroprotective and immunomodulatory effects. However, the underlying mechanisms linking salidroside, ferroptosis, and adaptive immunity in AD remain uncertain. The objective of this study is to explore the neuroprotective effects and the potential molecular mechanisms of salidroside against neuronal ferroptosis and CD8⁺ T cell infiltration in senescence-accelerated mouse prone 8 (SAMP8) mice. SAMP8 mice were employed as an AD model and were treated with salidroside for 12 weeks. Behavioral tests, immunohistochemistry, HE and Nissl staining, immunofluorescence, transmission electron microscopy, quantitative proteomics, bioinformatic analysis, flow cytometry, iron staining, western blotting, and molecular docking were performed. Treatment with salidroside dose-dependently attenuated cognitive impairment, reduced the accumulation of Aβ plaques and restored neuronal damage. Salidroside also suppressed the infiltration of CD8⁺T cells, oxidative stress, and inflammatory cytokines, and improved mitochondrial metabolism, iron metabolism, lipid metabolism, and redox in the SAMP8 mice brain. The administration of salidroside decreased iron deposition, reduced TFR1, and ACSL4 protein expression, upregulated SLC7A11, and GPX4 protein expression, and promoted the Nrf2/GPX4 axis activation. In conclusion, neuronal ferroptosis and CD8⁺T cells are involved in the process of cognitive impairment in SAMP8 mice. Salidroside alleviates cognitive impairment and inhibits neuronal ferroptosis. The underlying mechanisms may involve the Nrf2/GPX4 axis activation and reduction in CD8⁺T cells infiltration. This study provides some evidence for the roles of salidroside in adaptive immunity and neuronal ferroptosis in SAMP8 mice.

Background: Alzheimer’s disease (AD) is a neurodegenerative disease. Ferroptosis plays a critical role in neurodegenerative diseases. Nuclear factor E2-related factor 2 (Nrf2) is considered an important factor in ferroptosis. Studies have demonstrated that salidroside has a potential therapeutic effect on AD. The intrinsic effect of salidroside on ferroptosis is unclear. The purpose of this study was to investigate the protective effects and pharmacological mechanisms of salidroside on alleviating neuronal ferroptosis in Aβ₁₋₄₂-induced AD mice and glutamate-injured HT22 cells. Methods: HT22 cells were injured by glutamate (Glu), HT22 cells transfected with siRNA Nrf2, and Aβ₁₋₄₂-induced WT and Nrf2^−/−AD mice were treated with salidroside. The mitochondria ultrastructure, intracellular Fe²⁺, reactive oxygen species, mitochondrial membrane potential, and lipid peroxidation of HT22 cells were detected. Malondialdehyde, reduced glutathione, oxidized glutathione disulfide, and superoxide dismutase were measured. The novel object recognition test, Y-maze, and open field test were used to investigate the protective effects of salidroside on Aβ₁₋₄₂-induced WT and Nrf2^−/−AD mice. The protein expressions of PTGS2, GPX4, Nrf2, and HO1 in the hippocampus were investigated by Western blot. Results: Salidroside increased the cell viability and the level of MMP of Glu-injured HT22 cells, reduced the level of lipid peroxidation and ROS, and increased GPX4 and SLC7A11 protein expressions. These changes were not observed in siRNA Nrf2 transfected HT22 cells. Salidroside improved the ultrastructural changes in mitochondria of HT22 cells and Aβ₁₋₄₂-induced AD mice, but not in Aβ₁₋₄₂-induced Nrf2^−/−AD mice. Salidroside increased protein expression levels of GPX4, HO1, and NQO1 and decreased protein expression of PTGS2 in Aβ₁₋₄₂-induced AD mice but not in Aβ₁₋₄₂-induced Nrf2^−/−AD mice. Conclusions: Salidroside plays a neuroprotective role by inhibiting neuronal ferroptosis in Aβ₁₋₄₂-induced AD mice and Glu-injured HT22 cells, and its mechanism is related to activation of the Nrf2/HO1 signaling pathway. Graphical

Background: Alzheimer’s disease (AD) is a fatal neurodegenerative disease characterized by progressive cognitive decline and memory loss. However, several therapeutic approaches have shown unsatisfactory outcomes in the clinical setting. Thus, developing alternative therapies for the prevention and treatment of AD is critical. Salidroside (SAL) is critical, an herb-derived phenylpropanoid glycoside compound, has been shown to attenuate lipopolysaccharide (LPS)-induced cognitive impairment. However, the mechanism underlying its neuroprotective effects remains unclear. Here, we show that SAL has a therapeutic effect in the senescence-accelerated mouse prone 8 (SAMP8) strain, a reliable and stable mouse model of AD.Methods: SAMP8 mice were treated with SAL, donepezil (DNP) or saline, and cognitive behavioral impairments were assessed using the Morris water maze (MWM), Y maze, and open field test (OFT). Fecal samples were collected and analyzed by 16S rRNA sequencing on an Illumina MiSeq system. Brain samples were analyzed to detect beta-amyloid (Aβ) 1–42 (Aβ1-42) deposition by immunohistochemistry (IHC) and western blotting. The activation of microglia and neuroinflammatory cytokines was detected by immunofluorescence (IF), western blotting and qPCR. Serum was analyzed by a Mouse High Sensitivity T Cell Magnetic Bead Panel on a Luminex-MAGPIX multiplex immunoassay system.Results: Our results suggest that SAL effectively alleviated hippocampus-dependent memory impairment in the SAMP8 mice. SAL significantly 1) reduced toxic Aβ1-42 deposition; 2) reduced microglial activation and attenuated the levels of the proinflammatory factors IL-1β, IL-6, and TNF-α in the brain; 3) improved the gut barrier integrity and modified the gut microbiota (reversed the ratio of Bacteroidetes to Firmicutes and eliminated Clostridiales and Streptococcaceae, which may be associated with cognitive deficits); and 4) decreased the levels of proinflammatory cytokines, particularly IL-1α, IL-6, IL-17A and IL-12, in the peripheral circulation, as determined by a multiplex immunoassay.Conclusion: In summary, SAL reversed AD-related changes in SAMP8 mice, potentially by regulating the microbiota-gut-brain axis and modulating inflammation in both the peripheral circulation and central nervous system. Our results strongly suggest that SAL has a preventive effect on cognition-related changes in SAMP8 mice and highlight its value as a potential agent for drug development.

Renal fibrosis progression is closely associated with aging, which ultimately leads to renal dysfunction. Salidroside (SAL) is considered to have broad anti-aging effects. However, the roles and mechanisms of SAL in aging-related renal fibrosis remain unclear. The study aimed to evaluate the protective effects and mechanisms of SAL in SAMP8 mice. SAMP8 mice were administered with SAL and Ferrostatin-1 (Fer-1) for 12 weeks. Renal function, renal fibrosis, and ferroptosis in renal tissue were detected. The results showed that elevated blood urea nitrogen (BUN) and serum creatinine (SCr) levels significantly decreased, serum albumin (ALB) levels increased, and mesangial hyperplasia significantly reduced in the SAL group. SAL significantly reduced transforming growth factor-β (TGF-β) and α-smooth muscle actin (α-sma) levels in SAMP8 mice. SAL treatment significantly decreased lipid peroxidation in the kidneys, and regulated iron transport-related proteins and ferroptosis-related proteins. These results suggested that SAL delays renal aging and inhibits aging-related glomerular fibrosis by inhibiting ferroptosis in SAMP8 mice.

Liver fibrosis is pathological progression of chronic liver disease. Recent research has focused on the activation of hepatic stellate cells (HSCs), highlighting their potential as targets for mitigating fibrosis. While herbal medicines and natural active ingredients have shown promising anti-fibrotic effects in clinical treatments, the impact of Astragalin (Ag) remains unexplored. In this study, we established in vivo and in vitro studies, employing fluorescence probe staining, transmission electron microscopy, and various analytical techniques. The results demonstrated Ag operates within a wide range of safe therapeutic doses in zebrafish and effectively alleviates liver fibrosis. Further experiments demonstrated that Ag induced HSCs ferroptosis via this pathway, leading to iron overload and ultimately alleviating liver fibrosis. In general, this study demonstrated that Ag promotes HSCs ferroptosis through NCOA4-mediated ferritinophagy, clarifying its mechanism in treating liver fibrosis and positioning Ag as a promising candidate for future clinical interventions.