Pericyte degeneration causes white matter dysfunction in the mouse central nervous system

Area of Science:

• Neuroscience
• Vascular Biology
• Cell Biology

Background:

• Diffuse white-matter disease is common in elderly individuals with dementia.
• The underlying biological mechanisms of white-matter disease remain unclear.
• Small-vessel disease is a significant contributor to age-related cognitive decline.

Purpose of the Study:

• To elucidate the biological mechanisms of diffuse white-matter disease.
• To investigate the role of pericytes in white-matter integrity.
• To explore potential therapeutic targets for white-matter disease.

Main Methods:

• Utilized pericyte-deficient mouse models.
• Employed magnetic resonance imaging (MRI) for in vivo assessment.
• Conducted viral-based tract-tracing, behavioral tests, and tissue analysis.
• Investigated fibrinogen's role in cell cultures and in vivo.

Main Results:

• Pericyte degeneration led to disrupted white-matter microcirculation and reduced blood flow.
• Accumulation of fibrin(ogen) deposits triggered myelin, axon, and oligodendrocyte loss.
• Fibrinogen/fibrin initiated autophagy-dependent cell death in oligodendrocytes and pericytes.
• Systemic fibrinogen manipulation affected white-matter pathology in pericyte-deficient mice.

Conclusions:

• Pericytes are critical regulators of white-matter structure and function.
• Pericyte dysfunction contributes to white-matter damage via fibrin(ogen) accumulation.
• Findings suggest therapeutic potential in targeting fibrinogen for white-matter diseases.