Fanglian Chen

Background and purpose: The aging brain is particularly sensitive to alterations in selenium status. Selenium deficiency has been associated with impaired neural function, cognitive decline, and increased vulnerability to neurodegeneration. However, the molecular mechanisms that link selenium biology to brain aging remain poorly understood. Methods: We conducted a bibliometric analysis of 1,826 publications and identified brain-aging DEGs from public datasets. After intersecting these with selenium-related gene sets, we used machine-learning feature selection and SHAP/nomogram evaluation to prioritize core genes, validated findings in an independent cohort, performed immune-infiltration and gene-drug enrichment analyses, and confirmed age-related transcriptional and protein changes in mouse brain tissue. Results: Bibliometric analysis showed a steady increase in publications on selenium and aging over the past two decades, with major research hotspots focusing on oxidative stress, selenoproteins, and cognitive function, while the selenium-cognition relationship remains relatively underexplored. Intersection analysis identified seven potential targets linking selenium to brain aging, from which machine-learning feature selection prioritized three core genes (SP1, SEPHS2, and MSRB1) that were significantly differentially expressed in aged samples. SHAP and nomogram analyses indicated that SP1 and SEPHS2 were the main contributors to model discrimination. Animal experiments further confirmed increased SP1 and decreased SEPHS2 expression at both mRNA and protein levels in aged mouse brains, consistent with the bioinformatic findings. Conclusion: This study identifies SP1 and SEPHS2 as key genes linking selenium to brain aging, providing new insights into the role of selenium in brain aging and suggesting that these genes may represent potential biomarkers or therapeutic targets for brain aging and aging-related brain disorders.

Alzheimer’s disease (AD), the leading cause of dementia, is characterized by amyloid beta accumulation and tau pathology propagation. Nanomedicine, a discipline enabling targeted drug delivery with precision, holds significant promise in the treatment of neurodegenerative diseases. This review explores the diagnostic and therapeutic applications of nanomaterials in neurodegenerative diseases, particularly AD, emphasizing their properties and their role in modulating pathogenic proteins. Advances in the development of novel anti-AD nanomedicines and their clinical progress are also highlighted. Despite the growing potential of nanotechnology in AD therapy, a definitive cure remains elusive. The review further addresses the current challenges in the field of AD nanomedicines and outlines future research directions to propel their development.

Aging leads to neurodegenerative diseases, such as cognitive decline, which are induced by persistent chronic low‐grade inflammation in the brain driven by microglial activation. However, whether and how brain‐derived exosomes from aged mice (A‐exo) induce a pro‐inflammatory state and cellular senescence in microglia within the aging brain is poorly understood. Here, we report that brain‐derived exosomes from aged mice (A‐exo) cause cognitive decline in normal young mice, inducing microglial overactivation, lipid droplet accumulation, and senescence‐associated secretory phenotype (SASP) secretion. This abnormal microglial activity arises from the elevated expression of PTGDS in A‐exo due to mouse aging, resulting in increased central and peripheral D‐prostanoid receptor 1 (DP1) ligand PGD2 levels, which subsequently leads to sustained DP1 signaling activation. Consequently, this process promotes myeloid cell infiltration, cellular senescence, and cognitive decline by generating a senescent, pro‐inflammatory microglial phenotype. Blocking the DP1 receptor ameliorates A‐exo‐mediated microglial overactivation, myeloid cell infiltration, and cellular senescence. Strikingly, DP1 receptor blockade improves cellular senescence, neuroinflammation, and cognitive decline in aged mice. Our findings reveal a systemic mechanism underlying the sustained activation of microglia following brain aging, paving the way for improving chronic neuroinflammation, cellular senescence, and cognitive decline associated with aging.

Background and purpose: The role of PD-L1/PD-1 axis in IS remains controversial, with conflicting outcomes from systemic PD-1 or PD-L1 knockout models. These discrepancies underscore the complexity of PD-L1/PD-1 signaling and highlight the need to explore its cell-specific functions, particularly in neurons and microglia. Neurons, as the primary functional cells in the CNS, play a critical role in modulating local immune responses, yet their contribution to PD-L1/PD-1 signaling in IS is unknown. Furthermore, the mechanisms linking PD-L1/PD-1 to microglial polarization remain unclear. This study investigates whether targeted suppression of neuronal PD-L1 alleviates IS injury by modulating the PD-1/RFX1 axis and driving microglial polarization toward an anti-inflammatory phenotype. Methods: Middle cerebral artery occlusion (MCAO) was performed in mice to model IS. Neuronal PD-L1 was selectively suppressed using AAV. Microglial polarization, PD-1 and RFX1 expression, and neuroinflammation were assessed via flow cytometry, immunofluorescence, 4D-FastDIA proteomics, and qPCR/ELISA. In vitro, PD-1 knockdown BV2 cells and RFX1 overexpression models were established to validate mechanistic interactions. Results: Neuronal PD-L1 suppression reduced infarct volume, improved cerebral blood flow, and alleviated neurological deficits in ischemic stroke mice. Microglial PD-1 expression decreased significantly, accompanied by a phenotypic shift from pro-inflammatory to anti-inflammatory states. RFX1, exclusively expressed in microglia, was downregulated and identified as a key regulator of PD-1 and microglial polarization. In vitro, RFX1 overexpression reversed the anti-inflammatory effects of PD-1 knockdown, restoring pro-inflammatory cytokine levels. Critically, neuronal PD-L1 suppression spared peripheral immune cells, avoiding systemic immune disruption. These findings establish the PD-1/RFX1 axis as a central mediator of neuron-microglia crosstalk in IS neuroinflammation. Conclusion: Neuronal PD-L1 suppression attenuates IS injury by modulating the PD-1/RFX1 axis to promote anti-inflammatory microglial polarization. This study reveals a novel neuron-microglia crosstalk mechanism and highlights RFX1 as a therapeutic target for IS. The neuron-specific strategy overcomes limitations of systemic PD-L1/PD-1 inhibition, offering a precise and clinically translatable approach to mitigate neuroinflammation while preserving peripheral immune homeostasis.