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.

中文翻译：

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周细胞变性导致小鼠中枢神经系统白质功能障碍。

与小血管疾病和痴呆相关的弥漫性白质疾病在老年人中普遍存在。然而，其生物学机制仍然难以捉摸。使用周细胞缺陷小鼠、磁共振成像、基于病毒的纤维束追踪以及行为和组织分析，我们发现周细胞变性扰乱了白质微循环，导致有毒的血液源性纤维蛋白（原）沉积物和血液的积累-流量减少，引发髓磷脂、轴突和少突胶质细胞的损失。这扰乱了大脑回路，导致神经元损失发生之前白质功能缺陷。纤维蛋白原和纤维蛋白原纤维在少突胶质细胞和周细胞培养物中引发自噬依赖性细胞死亡，而周细胞缺陷小鼠而非对照小鼠中全身纤维蛋白原水平的药理学和遗传操作影响了白质纤维蛋白（原）沉积和周细胞变性的程度、血管病理学和白质变化。因此，我们的数据表明周细胞控制白质结构和功能，这对与小血管疾病相关的人类白质疾病的发病机制和治疗具有影响。