Down syndrome (DS) represents one of the most common genetic disorders attributable to a partial or complete trisomy of chromosome 21 that affects about 1 in 700 individuals at birth. The diagnosis of Alzheimer's Disease (AD)-correlated cognitive decline in this population requires new approaches and new biomarkers that comprehensively assess health status and early cognitive decline. In this observational study, we explored for the first time the relation of IL-18, a cytokine member of IL-1 family involved in both innate and acquired immune responses, with DS associated cognitive decline. We observed that plasma total IL-18, in subjects with DS over 35 with and without AD-related cognitive decline, and plasma concentrations of its binding protein in subjects with DS (19-35 years) were correlated with lower plasma concentrations of Transforming Growth Factor (TGF-β1), which are linked to an increased rate of cognitive decline in adults with DS. In addition, we found a significant association between low baseline concentrations of Free IL-18, the active form of the cytokine, and an increased rate of cognitive decline at 12 months, calculated as delta of the Test for Severe Impairment (dTSI), in individuals with DS (19-35 years). Finally, we demonstrated a reduction of Free IL-18/TNF-α ratio, considered as a new possible double biomarker, in both young and older adult DS subjects without AD-related cognitive decline (area under the receiver operating curve (AUC) was 0.82 and 0.71, respectively), suggesting the advantage of the composite biomarkers in the discrimination of patients from healthy people over single biomarkers.

Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly linked to neurodegeneration in Parkinson's disease (PD). The lipid-peroxidizing enzyme 5-lipoxygenase (5-LOX) contributes to ferroptotic stress, while montelukast, a leukotriene receptor antagonist widely used for asthma, indirectly interferes with this pathway. Here, we investigated whether montelukast protects against dopaminergic injury in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were evaluated for behavioral deficits and underwent histological and biochemical analyses to assess iron burden, oxidative stress, ferroptosis markers, and neuroinflammation. Montelukast administration alleviated MPTP-induced motor dysfunction, preserved tyrosine hydroxylase-positive neurons, and reduced α-synuclein accumulation. Treatment also decreased iron deposition and malondialdehyde production while restoring glutathione and superoxide dismutase activity. At the molecular level, montelukast upregulated xCT/GPX4 while downregulating ACSL4/5-LOX, indicating suppression of ferroptosis. Moreover, montelukast attenuated microglial activation and pro-inflammatory cytokine expression. Collectively, our results suggest that prophylactic administration of montelukast mitigates dopaminergic neurodegeneration by modulating markers of ferroptosis and inflammatory signaling. These findings indicate the GPX4/ACSL4/5-LOX axis as a potential neuroprotective target for PD.

Vascular dementia (VaD), a major contributor to cognitive decline, arises primarily from impaired regulation of cerebral circulation. Pterostilbene (PTE), a natural stilbene, exhibits potent neuroprotective properties, including antioxidative, anti-apoptotic, and cognition-enhancing effects; however, the molecular basis of its protective action in VaD remains poorly defined. Here, we integrated network pharmacology with in-vitro and in-vivo validation to delineate the mechanistic underpinnings of PTE. An ischemic injury model was established in SH-SY5Y cells using oxygen-glucose deprivation/reoxygenation (OGD/R), while VaD was induced in rats by bilateral common carotid artery occlusion. Cognitive function was assessed by behavioural paradigms, and neuronal integrity, vascular architecture, mitochondrial function, respiratory complex activities, and synaptic plasticity via the cAMP/PKA/CREB signalling cascade were evaluated using histological, biochemical, and molecular assays. Network pharmacology identified the cAMP pathway as a principal mediator of PTE activity. In ischemia injured SH-SY5Y cells, PTE improved viability, reduced oxidative stress, stabilized mitochondrial membrane potential, and elevated ATP production. In VaD rats, PTE enhanced spatial learning and memory, preserved cortical and hippocampal structures, and promoted mitochondrial health, evidenced by upregulation of PGC-1α and TFAM, restoration of respiratory complex activities, and preservation of mitochondrial ultrastructure. PTE also increased expression of synaptic proteins (PSD95, Synaptophysin). Consistently across both models, PTE activated the cAMP/PKA/CREB signalling axis. Collectively, these findings demonstrate that PTE mitigates ischemia-induced cognitive impairment by reversing mitochondrial dysfunction while sustaining synaptic plasticity through cAMP/PKA/CREB activation, highlighting its translational potential as a therapeutic candidate for VaD.

Chronic cerebral hypoperfusion (CCH) is a key pathological hallmark observable in multiple subtypes of cerebral small vessel disease (CSVD). This condition causes both structural and functional changes within the brain's vascular system, and is particularly damaging to brain microvascular endothelial cells (BMECs). The exact molecular mechanisms underlying BMEC impairment in CCH remain insufficiently defined despite their clinical importance. Emerging evidence indicates that disturbances in intracellular lipid metabolism might contribute substantially to promoting endothelial inflammation and functional deficits. This study aims to investigate whether aberrant lipid metabolism contributes to endothelial inflammation and tight junction (TJ) dysfunction in BMECs under the condition of CCH, and to assess the therapeutic potential of intervention with simvastatin. A rat model of chronic CSVD was created via permanent bilateral ligation of the common carotid arteries (2VO) in animal subjects. Samples of cortical microvasculature were collected at predefined intervals for transcriptome profiling. Assessments of lipid metabolism, inflammation-related factors, and TJ protein levels were conducted in both in vivo and after induction of hypoxia and administration of simvastatin. At 14d post-2VO, mRNA expression of TJ proteins including occludin (Ocln), claudin-5 (Cldn5), and zonula occludens-1 (Zo-1) was significantly downregulated in BMECs compared to sham controls. Simultaneously, there was a notable buildup of lipid droplets, rise in cholesterol levels, and upregulation of pro-inflammatory indicators including VCAM1, TNF-α, and ICAM1. Simvastatin administration effectively reduced lipid buildup, suppressed inflammation, and restored TJ integrity. Dysregulated lipid metabolism and heightened inflammatory responses contribute to TJ disruption in BMECs with CCH. Simvastatin therapy mitigates lipid accumulation, dampens inflammation, and improves TJ function in BMECs with CCH.

Neurodegenerative diseases impose a substantial and growing global burden, affecting millions worldwide and leading to high medical, social, and economic costs. These are characterized by progressive neuronal dysfunction and loss, leading to cognitive, motor, and behavioral impairments. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease are driven by intertwined mechanisms of oxidative stress, neuroinflammation, protein aggregation, and neuronal apoptosis. Activation of the TLR-2/NF-κB axis promotes neuroinflammation and pyroptotic cell death through excessive production of pro-inflammatory cytokines, contributing to neuronal damage. Dysregulation of the TLR-2/Akt/mTOR pathway impairs autophagy, leading to defective clearance and accumulation of α-synuclein, a central event in synucleinopathies. Moreover, compromised Nrf2-mediated antioxidant signaling weakens cellular redox homeostasis and anti-apoptotic defenses, thereby linking redox imbalance to caspase-dependent neuronal apoptosis. Given the complex and multifactorial nature of neurodegenerative diseases, there is a pressing need for multitarget agents. Phloretin is a natural dihydrochalcone predominantly found in apples, pears, and strawberries. It exhibits broad pharmacological activities, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects, making it a promising multitarget phytochemical for neurodegenerative conditions. Phloretin mediates its neuroprotective properties through the modulation of several mediators, including Aβ, TLR-2, NF-κB, COX, iNOS, PPARγ, Nrf2, beclin-1, Bax, Bcl-2, caspases, PI3K/Akt, mTOR, pro-inflammatory cytokines, and antioxidant enzymes, among others. Despite compelling preclinical evidence, critical gaps remain regarding phloretin's effects on inflammasome initiation, ER stress responses, mitophagy, neurotrophic signaling, and, importantly, its clinical safety and efficacy, underscoring the need for integrated mechanistic studies and well-designed clinical trials.