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A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology
Published on: March 17, 2016
Pericyte degeneration causes white matter dysfunction in the mouse central nervous system
Axel Montagne1,2, Angeliki M Nikolakopoulou1,2, Zhen Zhao1,2
1Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Abstract:
Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.
Insights
Pericyte degeneration disrupts white matter microcirculation, leading to myelin and axon loss in elderly dementia. Targeting fibrinogen may offer new therapeutic strategies for white matter diseases.
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.
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