Dataset Information

Biochemical and structural analysis of the interaction between ?-amyloid and fibrinogen.

ABSTRACT: The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with ?-amyloid (A?), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models. In this study, we investigated the biochemical and structural details of the A?-fibrinogen interaction. We identified the central region of A?42 as the most critical region for the interaction, which can be inhibited by specific antibodies against the central region of A? and by naturally occurring p3 peptides, A?17-40 and A?17-42. X-ray crystallographic analysis revealed that A?42 binding to fragment D of fibrinogen induced a structural change in the C-terminal region of the fibrinogen ?-chain (?384-393). Furthermore, we identified an additional A?-binding site within the ?C region of fibrinogen. A? binding to this ?C region blocked plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of a plasmin-resistant fibrin degradation fragment. Overall, our study elucidates the A?-fibrinogen interaction and clarifies the mechanism by which A?-fibrinogen binding delays fibrinolysis by plasmin. These results may facilitate the development of effective therapeutics against the A?-fibrinogen interaction to treat cerebrovascular abnormalities in AD.

SUBMITTER: Zamolodchikov D

PROVIDER: S-EPMC5000847 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen.

Zamolodchikov Daria D Berk-Rauch Hanna E HE Oren Deena A DA Stor Daniel S DS Singh Pradeep K PK Kawasaki Masanori M Aso Kazuyoshi K Strickland Sidney S Ahn Hyung Jin HJ

Blood 20160707 8

The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with β-amyloid (Aβ), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models. In this study, we investigated the biochemical and structural details of ...[more]

PMID: 27389717

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Project description:Essentials Evidence suggests a comorbidity between hyperhomocysteinemia (HHC) and Alzheimer's disease (AD). Homocysteine (HC) could affect the ?-amyloid (A?)-fibrinogen interaction in AD pathology. AD patients with concomitant HHC have increased fibrin and A? deposits in their brains. HC contributes to AD pathology via the A?-fibrinogen interaction.Background Accumulating clinical evidence suggests that hyperhomocysteinemia (HHC) is correlated with Alzheimer's disease (AD) and vascular dementia. Objective This study was carried out to elucidate the specific role of elevated homocysteine (HC) levels in AD pathophysiology. Methods Immunohistochemistry was used to examine ?-amyloid (A?) deposition along blood vessels, also known as cerebral amyloid angiopathy (CAA), fibrin(ogen) deposition, and their correlation to each other in the brains of AD patients with and without HHC. To study AD-HHC co-morbidity in detail, an AD mouse model was administered a high methionine diet for several months. Parenchymal A? plaques, CAA-positive vessels and fibrin deposits were then assessed by immunohistochemistry at different stages of AD progression. Memory deficits were evaluated with contextual fear conditioning and the Barnes maze. Additionally, the effect of HC and its metabolite, homocysteine thiolactone (HCTL), on the A?-fibrinogen interaction was analyzed by pull-down, ELISA and fibrin clot formation and fibrinolysis assays in vitro. Results We found increased fibrin(ogen) levels and A? deposits in the blood vessels and brain parenchyma of AD patients with HHC. We demonstrate that HC and HCTL enhance the interaction between fibrinogen and A?, promote the formation of tighter fibrin clots and delay clot fibrinolysis. Additionally, we show that diet-induced HHC in an AD mouse model leads to severe CAA and parenchymal A? deposition, as well as significant impairments in learning and memory. Conclusions These findings suggest that elevated levels of plasma HC/HCTL contribute to AD pathology via the A?-fibrin(ogen) interaction.

Dataset Information

Biochemical and structural analysis of the interaction between ?-amyloid and fibrinogen.

Publications

Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen.

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