Ulcerative colitis (UC) is increasingly associated with central nervous system comorbidities, including cognitive decline and dementia, yet the molecular mechanisms linking intestinal inflammation to brain dysfunction remain unclear. Blood–brain barrier (BBB) disruption is a plausible convergence point, but the mediators involved are largely unknown. We performed random-effects meta-analyses of five human UC bulk-transcriptome cohorts (1,130 UC and 508 control samples) and three mouse BBB-disruption (BBBD) cohorts, followed by cross-species orthologue mapping to identify shared genes. The cellular context of candidate genes was resolved by single-cell RNA-sequencing analysis of human UC colonic mucosa (GSE214695) and paired human BBB-intact/BBB-opened brain samples (GSE208074), combined with scTenifoldKnk in-silico gene knockout. Summary-data-based Mendelian randomization (SMR) integrating whole-blood cis-eQTL and FinnGen GWAS data was used to assess causal relevance to dementia. Findings were validated in dextran sulfate sodium (DSS)-induced colitis in mice preventively treated with the ADAM17 inhibitor GW280264X, with Evans blue assessment of BBB permeability. Four genes—TNF, RHBDF2, PILRA and CXCL16—were significantly and concordantly up-regulated in both UC and BBBD, forming a protein–protein association module organized around the sheddase ADAM17. RHBDF2, the essential activating chaperone of ADAM17, was predominantly up-regulated in colonic epithelial cells in UC, whereas its strongest inferred regulatory impact at the human BBB mapped to endothelial cells, affecting complement, microglial and angiogenic programs. Genetically predicted higher expression of RHBDF2 and PILRA was associated with increased risk of all-cause and Alzheimer’s dementia. In DSS-induced colitis, preventive administration of GW280264X attenuated intestinal inflammation, reduced cerebral Evans blue extravasation and lowered brain Rhbdf2, Adam17 and Tnfα protein levels. Integrative transcriptomic, genetic and experimental evidence identifies an RHBDF2–ADAM17–TNFα axis as a plausible mechanistic bridge between ulcerative colitis and blood–brain barrier disruption and a candidate therapeutic target.
In developmental and epileptic encephalopathies (DEEs), the seizure phenotype is rarely static. Infantile epileptic spasms typically subside and are often replaced years later by other seizure types, and in several genetically defined DEEs seizure-free intervals precede seizure recurrence. Although these transitions are linked to long-term outcome, little is known about the molecular and cellular events that accompany them, because the interval is clinically silent and brain tissue is inaccessible. Animal studies have only partly filled this gap: most DEE models have been characterized at a single age, and models with continuous seizures provide no interval to investigate. We recently performed time-resolved deep phenotyping of Cyfip2 +/R87C mice, which recapitulate neonatal seizure-like events, a prolonged seizure-free interval, and adult-onset spontaneous recurrent seizures with premature death, using transcriptomic, ultrastructural, proteomic, and lipidomic analyses across four postnatal stages. Here we summarize the temporal landscape: excitatory synapse number falls while remaining synapses relocate to dendritic shafts, oligodendrocyte-lineage cells, microglia, and astrocytes are engaged sequentially, and lipid droplets accumulate progressively in astrocytes. We also highlight what remains unresolved. The highest-resolution analyses were performed only after seizure recurrence, illustrating a tradeoff between analytical depth and temporal coverage, so the juvenile interval preceding recurrence remains the central knowledge gap. Even so, the emerging picture is that the seizure-free interval is not a period of quiescence but one of active neuron–glia and metabolic remodeling. Defining this interval more precisely, and identifying biomarkers for patient staging, may transform a clinically silent phase into a well-defined therapeutic window for stage-specific intervention.
Gerardo Medina, Stephen D. Baird, Lilia A. Rodriguez-Alcocer, Alex E. MacKenzie
Docosahexaenoic acid (DHA), the predominant omega-3 (ω-3) fatty acid in the brain, which contributes to synaptic membrane organization and plasticity, is commonly recommended for brain health. However, ω-3 formulations commonly combine DHA with eicosapentaenoic acid (EPA) in varying proportions, and the impact of the DHA ratio on postsynaptic scaffold regulation remains unclear. In this study, differentiated human SH-SY5Y neurons were cultured in the presence of DHA, EPA, or defined DHA ratios (2:1, 1:1, 1:2) at equivalent total concentrations. PSD-95 expression, puncta density, colocalization with the presynaptic marker synaptophysin (SYN), and glutamatergic signaling proteins were quantified by immunofluorescence and Western blot analysis. Metabolic activity was assessed using a colorimetric MTT assay. DHA produced the largest increase in PSD-95 protein abundance by immunoblot and the strongest effects on PSD-95 puncta density and SYN colocalization, accompanied by coordinated upregulation of N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and calcium/calmodulin-dependent protein kinase II (CaMKII). DHA-enriched compositions preserved this profile, whereas balanced or EPA-dominant compositions showed attenuated responses relative to DHA-dominant conditions. EPA alone failed to enhance postsynaptic scaffold abundance and reduced NMDAR levels relative to control. These effects occurred without a detectable reduction in cellular metabolic activity. Collectively, these findings demonstrate that the composition of ω-3 fatty acid has a significant bearing on postsynaptic scaffold organization and glutamatergic signaling in differentiated neurons, with DHA serving as the chief mediator of observed effects. This composition-dependent framework provides an experimental basis for considering DHA ratio when evaluating omega-3 effects on postsynaptic protein organization.
