The role of blood-brain barrier integrity in depression
Gál Zsófia
Gyógyszertudományok és Egészségügyi Technológiák Tagozat
Dr. Zelkó Romána
NET 5. szemináriumi terem
2025-07-18 13:00:00
Experimental and Clinical Pharmacology
Dr. Szökő Éva
Dr. Bagdy György és Dr. Petschner Péter
Dr. Szabó-Vereczkei Andrea
Dr. Tóth Erzsébet Melinda
Dr. Purebl György
Dr. Béni Szabolcs
Dr. Farkas Kinga
Previous results from animal studies highlighted the important role of the blood-brain barrier (BBB) and inflammatory factors in stress-associated depression. Our aims were to prove these pathomechanisms, specifically, the role of BBB and inflammation in stress-associated depression with two different genomic approaches in humans. In the first study a hypothesis-driven, candidate gene approach was used to translate evidences to humans from rodent studies, which indicated that reduced expression of tight junction protein claudin-5 after chronic stress, might weaken the BBB and allow interleukin-6 to infiltrate the central nervous system from the periphery, inducing depressive symptoms. Three-way interaction of functional polymorphisms rs885985 of CLDN5 gene and rs1800795 of IL6 gene, and recent stressful life events were tested on current depressive symptoms. Further characterizations were also conducted in order to reveal potential sex differences and to uncover the possible individual effects of the polymorphisms. The 3-way interaction including recent stress yielded highly significant results on current depressive symptoms, which was more pronounced in men and could be replicated on trend level in an independent cohort. None of any other interactions, including childhood stressors and lifetime depression as an outcome, yielded significance.
In the second study, a genome-wide by environment interaction analysis (GWEIS) was conducted on 6.26 M genetic variants covering 19,296 genes on PHQ9 depression phenotype in interaction with adult traumatic events scores. Among the 63 genes that remained significant after correction for multiple testing, 17 were associated with BBB, 23 with inflammatory processes, and 4 with neuroticism. Altogether, 4 genes remained significant in the whole cohort, in men, and in women, separately: CSMD1, PTPRD, NPAS3, and LSAMP. Compared to all genes, the enrichment of significant BBB-associated genes was 3.82, and that of inflammation-associated genes was 1.59, with both being statistically different from the expected ratio.
In conclusion, both studies confirmed a strong role of BBB and inflammation in stress-associated depression, and the identified risk genes and their encoded proteins could serve as biomarkers or new drug targets to promote BBB integrity to prevent or decrease stress- and inflammation-associated depressive symptoms.
