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Cerebral amyloid angiopathy-linked ?-amyloid mutations promote cerebral fibrin deposits via increased binding affinity for fibrinogen.

ABSTRACT: Cerebral amyloid angiopathy (CAA), where beta-amyloid (A?) 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?) peptide cause an increase in vascular deposits. Since the interaction between A? and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, we investigated the role of the A?-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? for fibrinogen. In addition, the stronger interaction between fibrinogen and mutant A?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? 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?, which might be central to cerebrovascular pathologies observed in HCAA.

SUBMITTER: Cajamarca SA

PROVIDER: S-EPMC7322009 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Cerebral amyloid angiopathy-linked β-amyloid mutations promote cerebral fibrin deposits via increased binding affinity for fibrinogen.

Cajamarca Steven A SA Norris Erin H EH van der Weerd Louise L Strickland Sidney S Ahn Hyung Jin HJ

Proceedings of the National Academy of Sciences of the United States of America 20200609 25

Cerebral amyloid angiopathy (CAA), where beta-amyloid (Aβ) 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 (Aβ) peptide cause an increase in vascular deposits. Since the interaction between Aβ and fibrino ...[more]

PMID: 32518112

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Project description:Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid ?-protein (A?)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular A? deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2(*) imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of A?40 for CAA and anti-A? antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by A? immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis, treatment, risk factors, and future perspectives.

Dataset Information

Cerebral amyloid angiopathy-linked ?-amyloid mutations promote cerebral fibrin deposits via increased binding affinity for fibrinogen.

Publications

Cerebral amyloid angiopathy-linked β-amyloid mutations promote cerebral fibrin deposits via increased binding affinity for fibrinogen.

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