Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n = 21) and healthy controls (n = 16), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P = 0.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.

Intracerebral hemorrhage (ICH) is a health challenge resulting in death or disability. Iron overload has been identified as one of post-ICH damaging factors. However, the impact of iron overload, as well as the underlying mechanisms, on neural stem/progenitor cells (NSPCs) remains unknown. In this study, we found that iron overload induced significant NSPC death in a dose-dependent manner. Interestingly, iron overload increased the number of early and late apoptotic cells and the expression of caspase-3 in NSPCs. Moreover, iron overload was highly correlated with enhanced intracellular reactive oxygen species (ROS) generation and loss of mitochondrial integrity. Further, iron overload activated mTOR signaling and downregulated AMP-activated protein kinase (AMPK) phosphorylation. Importantly, drugs that eliminate ROS or activate AMPK prevented this event, as well as apoptosis of NSPCs. These results indicate that post-ICH iron overload in the brain induces excessive ROS generation and leads to NSPC death by regulating mTOR and AMPK signaling.

Due to delayed symptoms and dependence of behavioral assessment, early diagnosis of autism spectrum disorder remains challenging. Identification of multivariate biomarker for the etiological mechanisms of ASD may enhance diagnostic accuracy. Multivariable logistic regression combines many predictors into a single risk score (linear predictor), resulting in an optimised ROC curve that enhances diagnostic accuracy over individual markers. The method comprises modelling a binary result, determining the likelihood, and visualising ROC based on the projected probabilities, which often improves individual marker AUCs. In the present study a diagnostic performance for a biomarker panel reflecting glutamatergic dysfunction, oxidative stress, and neuroinflammation was evaluated. Plasma levels of glutaminase, 8-isoprostane, and prostaglandin E₂ (PGE₂) obtained from 44 children with ASD and 40 age-matched controls were evaluated using receiver operating characteristic (ROC) analysis, both individually and in combined ROC models. Glutaminase showed significant negative correlations with both 8-isoprostane and PGE₂, whereas a positive correlation was observed between 8-isoprostane and PGE₂. All the three-biomarker showed good diagnostic performance for ASD on its own with statistically significant (p = 0.001) values of AUC of 0.830 for glutaminase, AUC of 0.815 for 8-Isoprostane and AUC of 0.818 for PGE₂. However combined ROC modeling substantially improved diagnostic accuracy by achieving high apparent discriminative performance with AUC value of 0.977 with 92.3% sensitivity and 100.0% specificity. In conclusion, the diagnostic usefulness of independent glutaminase, 8-isoprostane, and prostaglandin E₂ (PGE₂) biomarkers may be enhanced by combining ROC. Combined markers show strong apparent discriminating power in a case-control method, but estimates are biassed towards optimism and are not diagnostic. Comprehensive assay validation, calibration, and clinically representative cohorts (including females and relevant differentials) are required for replication.

The CHRNA7 gene, located on chromosome 15q13.3, encodes the α7 nicotinic acetylcholine receptor (α7 nAChR) subunit and lies within a genomic region characterized by high recombination rates and associations with multiple neuropsychiatric disorders. Within this region, the human specific gene CHRFAM7A arose through partial duplication, rearrangement, and fusion between CHRNA7 and FAM7A. The direct CHRFAM7A allele has been shown to negatively regulate α7 nAChR function. The inverted allele (CHRFAM7AΔ2bp), harboring a two-base pair deletion in exon 6, is linked to schizophrenia, bipolar disorder, and other psychiatric conditions. In this study, we investigated how the presence of the CHRFAM7AΔ2bp allele alters the cellular proteome. Using high-throughput proteomic analysis by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), we characterized protein expression in neuronal progenitors differentiated from isogenic human induced pluripotent stem cell (iPSC) lines representing CHRFAM7AΔ2bp and CHRFAM7A-null genotypes. Comparative analysis identified 129 differentially expressed proteins enriched in pathways related to extracellular matrix organization, collagen biosynthesis, and cell adhesion. Functional assays further demonstrated differences in matrix adhesion between CHRFAM7A-null and CHRFAM7AΔ2bp-derived progenitors. These results suggest that the CHRFAM7AΔ2bp variant influences cellular structure through modulation of adhesion matrix-interaction proteins. This work provides insight into molecular mechanisms that may underlie increased neurodisease vulnerability associated with this genotype.

Cerebral toxoplasmosis is a common opportunistic parasitic infection of the CNS caused by the Toxoplasma gondii parasite. Host immunosuppression can affect disease outcomes. To explore the changes in the cerebral cortical ultrastructure accompanying the infection in different immune-altered models and to find an effective treatment against the infection, we tested the possible therapeutic effect of clofazimine (CFZ) (the FDA-approved antimycobacterial drug) against the infection using 60 male CD1 Swiss Albino mice divided into 6 groups: 3 dexamethasone (DEX)- treated groups (DEX-only, DEX-infected, and DEX-infected-treated), and 3 streptozotocin (STZ)-induced type 1 diabetic groups (STZ-only, STZ-infected, STZ-infected-treated). The worst ultrastructural changes were observed in the diabetic and diabetic-infected groups, characterized by a significant increase in neuronal apoptotic and necrotic nuclei (P < 0.05) and changes in the numbers and structure of glial cells compared to the DEX and DEX-infected groups. CFZ (at a dose of 10 mg/kg/day for 3 days starting on 45th day post infection) significantly improved cortical neuronal ultrastructural changes in both models (P < 0.05), reduced microglial numbers, increased astrocyte numbers, and restored brain capillary integrity and axonal growth, in addition to significantly reducing mature cyst numbers in both models (P < 0.05). However, the drug didn't reduce the number of atrophic and necrotic cysts in the infected-treated groups. So, in our study, CFZ showed preclinical promise in treating experimental cerebral toxoplasmosis and reducing the parasitic cyst burden, highlighting the adverse impact of the host's altered immune status on brain tissue and the course of the infection, especially in diabetes.

The intersection of age- and experience-dependent processes influence learning throughout development, and developmental learning can have long-term effects on behavior. Phosphorylation of ribosomal protein S6 phosphorylation (pS6) is required in active ribosomes, and new protein synthesis is a conserved mechanism that supports long term memory formation. As such, pS6 fluctuations in brain regions processing experience can provide insight into shifts in the ability for learning and memory. Juvenile male and female zebra finch songbirds (Taeniopygia guttata) perform sensory song learning in ways that affect their adult behaviors. As adults, both sexes perform song recognition learning. Both juvenile and adult types of sensory learning invoke the auditory forebrain. Prior reports established a pS6 song response in the auditory forebrain in Posthatch day 30 juvenile males but not females, and not in younger birds. This was intriguing because the experience-dependent pS6 increase tracked with the onset of the critical period for juvenile sensory song learning in males, and behavioral data indicated that females also effectively learn at P30, though they may not have a critical period. Further, by adulthood (> Posthatch day 90), both male and female auditory forebrains showed an equivalent increase in pS6 after hearing song in patterns consistent with effective recognition learning. Here, to further test the relationships between a crucial molecular marker of active learning processes and the developmental trajectory of juvenile sensory song learning and the emergence of adult-like song recognition learning, we assessed the effect of age and sex, as well as the absence of tutor experience, a manipulation that extends the critical period for developmental learning in males, on the phosphorylation of S6 within the auditory forebrain. Outcomes highlight the complexity of molecular mechanisms across developmental learning and reveal questions to be addressed by further inquiry.

Overexpression of Sxc-, a cystine/glutamate antiporter is implicated in several neurological disorders including epilepsy. Physiologically, it regulates the hippocampal synaptic glutamate pool, influencing the neuronal excitability. Sulfasalazine (SAS) recently garnered interest owing to its system xc- (Sxc-) inhibitory potential. Therefore, the current study investigated the effects of SAS in two distinct models, (i) maximal electroshock (MES) induced acute seizure model and (ii) Pentylenetetrazol (PTZ) induced kindling model of chronic epilepsy and associated cognitive impairment. Initially, rats treated with different doses of SAS (25- 200 mg/kg, i.p.) for 7 days were subjected to MES and observed for seizures. SAS 50 mg/kg improved the extension-to-flexion ratio (E/F ratio) in MES induced seizures and exhibited neuroprotection, whereas the higher doses failed. In another experiment, mice were treated with PTZ (35 mg/kg) on alternate days for 24 days to induce kindling. SAS (50 or 100 mg/kg, i.p.) or vehicle was administered daily, 30 min prior to each PTZ injection. Seizures were monitored for 30 min following PTZ injection. Chronic PTZ administration led to progressively increased seizure severity, culminating in generalized tonic-clonic seizures in mice. SAS 100 mg/kg treatment reduced stage 4 and 5 seizure scores and improved spatial retention memory in mice. SAS also significantly attenuated the gene expression of inflammatory cytokines, TNF-α, IL-1β, and IL-6, and mitigated neuronal damage induced by epileptic kindling. Altogether, results suggest that SAS exhibits anti-epileptic effects, reduces neuroinflammation, and alleviates cognitive dysfunction in the PTZ kindling model of epilepsy in mice.