Transcriptomic and experimental validation identifies SOX6 and LDLRAD3 as key factors in vascular dementia

Area of Science:

• Neuroscience
• Genomics
• Cell Biology

Background:

• Vascular dementia (VaD) is a major cause of cognitive decline with poorly understood molecular underpinnings.
• Understanding cellular and molecular changes in VaD is crucial for developing effective treatments.

Purpose of the Study:

• To investigate molecular alterations in neuronal and endothelial cells in vascular dementia (VaD).
• To identify key genes and pathways involved in VaD pathogenesis using integrated multi-omics data.

Main Methods:

• Integrated single-nucleus RNA sequencing (snRNA-seq) and microarray data from postmortem VaD brain tissues.
• Applied high-dimensional weighted gene co-expression network analysis (hdWGCNA) and machine learning.
• Validated findings in a mouse model of ischemic stroke (transient middle cerebral artery occlusion - tMCAO).

Main Results:

• SOX6 identified as a key gene in neurons; LDLRAD3 identified in endothelial cells associated with VaD.
• Neuronal pathways implicated include glutamatergic synapses and MAPK signaling.
• Endothelial cell pathways involve MAPK signaling, lipid metabolism, and atherosclerosis.
• SOX6 and LDLRAD3 expression was upregulated in a mouse model of VaD.

Conclusions:

• SOX6 and LDLRAD3 are critical molecular players in vascular dementia (VaD).
• Neuronal and endothelial cell interactions, particularly MAPK signaling and lipid metabolism, are vital in VaD progression.
• These genes and pathways represent potential therapeutic targets for VaD treatment.