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Microglia-Derived Vitamin D Binding Protein Mediates Synaptic Damage and Induces Depression by Binding to the

Yan Kong1,2, Xian Zhang1, Ling Li1

  • 1Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 24, 2024
PubMed

Insights

Vitamin D binding protein (VDBP) from microglia drives depression-like behaviors by damaging neurons. Targeting this VDBP offers a new therapeutic strategy for major depressive disorder (MDD).

Area of Science:

  • Neuroscience
  • Psychiatry
  • Molecular Biology

Background:

  • Major depressive disorder (MDD) lacks definitive biomarkers.
  • Vitamin D binding protein (VDBP) is implicated as a potential MDD biomarker.
  • The role of VDBP in the neurobiology of depression is not fully understood.

Purpose of the Study:

  • To investigate the role of microglia-derived VDBP in depression-like behaviors.
  • To elucidate the molecular mechanisms linking VDBP to neuronal damage in MDD.
  • To identify VDBP as a potential therapeutic target for MDD.

Main Methods:

  • Utilized a chronic unpredictable mild stress (CUMS) mouse model.
  • Examined VDBP expression in brain regions related to emotion.
  • Employed conditional knockout strategies for microglia-derived VDBP.
  • Investigated the interaction between VDBP, megalin, and the SRC signaling pathway.

Main Results:

  • VDBP is highly expressed in emotion-related brain regions in CUMS mice.
  • Overexpression of microglia-derived VDBP induced depression-like behaviors and neuronal damage.
  • Conditional knockout of microglia-derived VDBP reversed these effects.
  • VDBP binding to megalin activated SRC signaling, causing neuronal and synaptic damage.

Conclusions:

  • Microglia-derived VDBP is a key mediator in MDD pathogenesis.
  • The VDBP-megalin-SRC pathway contributes to neuronal damage and depression-like behaviors.
  • Targeting microglia-derived VDBP presents a promising therapeutic avenue for MDD.
Keywords:
depressionmegalinmicroglianeuron damagevitamin D binding protein

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