Cerebral amyloid angiopathy-linked β-amyloid mutations promote cerebral fibrin deposits via increased binding affinity for fibrinogen
Cerebral amyloid angiopathy-linked β-amyloid mutations promote cerebral fibrin deposits via increased binding affinity for fibrinogen
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DOI：
10.1073/pnas.1921327117
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发表时间：
2020-06-23
影响因子：
11.1
通讯作者：
Ahn, Hyung Jin
中科院分区：
文献类型：
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作者：
Cajamarca, Steven A.;Norris, Erin H.;Ahn, Hyung Jin
脑淀粉样血管病（CAA），其中β-淀粉样蛋白（A β）沉积在脑血管周围，是阿尔茨海默病（AD）患者血管功能障碍的主要原因。然而，CAA形成和CAA诱导的脑血管病变的分子机制尚不清楚。遗传性脑淀粉样血管病（HCAA）是一种罕见的CAA家族性形式，其中（A β）肽内的突变导致血管沉积物增加。由于A β和纤维蛋白原之间的相互作用增加CAA并在AD的脑血管损伤中起重要作用，因此我们研究了A β-纤维蛋白原相互作用在HCAA病理中的作用。我们的工作揭示了最常见的HCAA连锁突变形式，荷兰（E22 Q）和爱荷华州（D23 N），导致A β与纤维蛋白原的结合亲和力增强50倍。此外，纤维蛋白原和突变A β之间更强的相互作用导致凝块结构的剧烈扰动和延迟的纤维蛋白溶解。枕叶皮质的免疫荧光分析显示，与早发性AD患者和非痴呆患者相比，HCAA患者的纤维蛋白（原）/A β共沉积以及纤维蛋白沉积增加。我们的研究结果表明HCAA型荷兰和爱荷华州突变增加了纤维蛋白原和A β之间的相互作用，这可能是在HCAA中观察到的脑血管病变的核心。
Cerebral amyloid angiopathy (CAA), where beta-amyloid (A beta)deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in Alzheimer's disease (AD) patients. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. Hereditary cerebral amyloid angiopathy (HCAA) is a rare familial form of CAA in which mutations within the (A beta) peptide cause an increase in vascular deposits. Since the interaction between A beta and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, we investigated the role of the A beta-fibrinogen interaction in HCAA pathology. Our work revealed the most common forms of HCAA-linked mutations, Dutch (E22Q) and Iowa (D23N), resulted in up to a 50-fold stronger binding affinity of A beta for fibrinogen. In addition, the stronger interaction between fibrinogen and mutant A beta s led to a dramatic perturbation of clot structure and delayed fibrinolysis. Immunofluorescence analysis of the occipital cortex showed an increase of fibrin(ogen)/A beta codeposition, as well as fibrin deposits in HCAA patients, compared to early-onset AD patients and nondemented individuals. Our results suggest the HCAA-type Dutch and Iowa mutations increase the interaction between fibrinogen and A beta, which might be central to cerebrovascular pathologies observed in HCAA.