Association of Α-Klotho with regulation of Keap1/Nrf2/Interleukin-1 pathway and AMPA receptor trafficking in the brain of suicide victims.
J Physiol Pharmacol
; 75(3)2024 Jun.
Article
in En
| MEDLINE
| ID: mdl-39042386
ABSTRACT
Suicide is a significant public health challenge worldwide. Statistical data confirm a strong relationship between suicidal behavior and depressive disorders (DDs), but the molecular mechanisms of these diseases are still poorly understood. A growing body of research suggests that the Klotho-mediated pathway may be a novel intracellular target for the development of suicide-related disorders (including DDs). To verify this hypothesis, the link between α-Klotho levels, Nrf2-related inflammatory status (IL-1α, IL-1ß, Keap1, NFκB p65), AMPA (GluA1, GluA2, p-S831-GluA1, p-S845-GluA1) receptor subunit trafficking and AMPK (AMPKα1/2; pT172-AMPKα1) signalling pathways in the brain of suicide victims as compared to controls were investigated. Commercially available enzyme-linked immunoassay (ELISA) and Western blot analysis were performed in the hippocampus (HP) and frontal cortex (FCx) of suicide victims and matched controls. Group differences were assessed using an unpaired Student's t-test. A statistically significant decrease in the level of α-Klotho (HP p=0.001; FCx p=0.012) with an increase in IL-1ß (HP p=0.0108) and IL-1α (FCx p=0.009) concentrations were shown. These alterations were associated with increased Keap1 (FCx p=0.023) and NF-κB-p65 (HP p=0.039; FCx p=0.013 nuclear fraction) protein levels. Furthermore, a significant reduction in p-S831-GluA1 (HP p=0.029; FCx=0.002) and p-S845-GluA1 (HP p=0.0012) proteins was observed. Similarly, the level of GluA2 (HP p=0.011; FCx p=0.002) and in p-T172-AMPKα1 (HP p=0.0288; FCx p=0.0338) protein were statistically decreased. Our findings demonstrate that a reduction in α-Klotho levels in brain structures related to mood disorders (HP, FCx) correlates with suicidal behavior. Moreover, our study provides novel insights into the molecular mechanisms underlying suicide-related disorders, highlighting the role of α-Klotho, Nrf2-related inflammatory status, AMPA receptor trafficking, and AMPK signaling pathways in the pathophysiology of suicidal behavior. These results may have implications for the development of targeted interventions for individuals at risk of suicide.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Suicide
/
Signal Transduction
/
Receptors, AMPA
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NF-E2-Related Factor 2
/
Kelch-Like ECH-Associated Protein 1
/
Klotho Proteins
/
Glucuronidase
Limits:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
J Physiol Pharmacol
Journal subject:
FARMACOLOGIA
/
FISIOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
Polonia
Country of publication:
Polonia