High levels of copper lead to cognitive impairment in major depressive disorder by inhibiting lncRNA NEAT1 and mitochondrial autophagy.

BACKGROUND

Major depressive disorder (MDD) is a prevalent category of affective mental disorders with a high incidence. Cognitive impairment is prevalent in MDD patients, and its underlying pathogenic mechanisms have not yet been fully clarified.

METHODS

We elevated copper levels in hippocampal neurons and quantified the expression of lncRNA NEAT1 as well as mitochondrial autophagy. Chronic restraint stress paradigm was applied to C57/BL6J mice to establish depression-like behaviors in mice (referred to as stress mice), with untreated C57/BL6J mice serving as naive controls. Additionally, we lowered copper levels in stress mice and assessed the expression of lncRNA NEAT1, mitochondrial autophagy, and memory performance. Serum copper levels and cognitive function scores were compared between MDD patients and healthy controls. We further evaluated the sensitivity and specificity of serum copper levels as a diagnostic marker for cognitive impairment in MDD patients.

RESULTS

High levels of copper suppressed lncRNA NEAT1 expression and mitochondrial autophagy in hippocampal neurons. Additionally elevated lncRNA NEAT1 levels lead to increased mitochondrial autophagy in hippocampal neurons. High levels of copper cause impaired memory in stress mice. Reducing copper levels could improve memory in stress mice. MDD patients exhibited higher serum copper levels and lower cognitive function scores compared with healthy controls. High levels of copper and decreased cognitive function scores exhibited a significant correlation in MDD patients. High levels of copper demonstrated favorable sensitivity and specificity for diagnosing cognitive impairment in MDD patients.

CONCLUSION

Our findings indicate that high levels of copper could impair mitochondrial autophagy by inhibiting lncRNA NEAT1 expression and contribute to cognitive impairment in MDD. High levels of copper may serve as a promising diagnostic biomarker for cognitive impairment in MDD patients.