Abstract:
Pathologies of the brain microvasculature, often referred to as cerebral small-vessel disease, are important contributors to vascular dementia, the second most common form of dementia in aging societies. In addition to their role in acute ischemic and hemorrhagic stroke, they have emerged as major cause of age-related cognitive decline in asymptomatic individuals. A central histological finding in these pathologies is the disruption of the vessel architecture including thickening of the vessel wall, narrowing of the vessel lumen and massive expansion of the mural extracellular matrix. The underlying molecular mechanisms are largely unknown, but from the investigation of several disease forms with defined etiology, high temperature requirement protein A1 (HTRA1), a secreted serine protease degrading primarily matrisomal substrates, has emerged as critical factor and potential therapeutic target. A genetically induced loss of HTRA1 function in humans is associated with cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), a rare, hereditary form of brain microvascular disease. Recently, proteomic studies on cerebral amyloid angiopathy (CAA), a common cause of age-related dementia, and cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most prevalent monogenic small-vessel disease, have provided evidence for an impairment of HTRA1 activity through sequestration into pathological protein deposits, suggesting an alternative mechanism of HTRA1 inactivation and expanding the range of diseases with HTRA1 involvement. Further investigations of the mechanisms of HTRA1 regulation in the brain microvasculature might spawn novel strategies for the treatment of small-vessel pathologies.
摘要:
脑微脉管系统的病理,通常被称为脑小血管疾病,是血管性痴呆的重要因素,老龄化社会中第二常见的痴呆症。除了它们在急性缺血性和出血性中风中的作用外,它们已成为无症状个体年龄相关认知功能下降的主要原因.这些病理的主要组织学发现是血管结构的破坏,包括血管壁的增厚,血管腔变窄和壁细胞外基质大量扩张。潜在的分子机制在很大程度上是未知的,但是从几种病因明确的疾病形式的调查来看,高温需求蛋白A1(HTRA1),一种分泌的丝氨酸蛋白酶,主要降解基质,已成为关键因素和潜在的治疗靶点。人类中遗传诱导的HTRA1功能丧失与伴有皮质下梗塞和白质脑病(CARASIL)的常染色体隐性遗传性脑动脉病有关,一种罕见的,遗传性脑微血管疾病。最近,脑淀粉样血管病(CAA)的蛋白质组学研究,与年龄有关的痴呆的常见原因,和伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(CADASIL),最普遍的单基因小血管疾病,通过隔离到病理蛋白沉积物中,提供了HTRA1活性受损的证据,提示HTRA1失活的替代机制,并扩大HTRA1参与的疾病范围。对脑微血管中HTRA1调节机制的进一步研究可能会产生治疗小血管病变的新策略。