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Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the beta-amyloid peptide (Abeta) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Abeta are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Abeta to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.

SUBMITTER: Cortes-Canteli M

PROVIDER: S-EPMC2895773 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease.

Cortes-Canteli Marta M Paul Justin J Norris Erin H EH Bronstein Robert R Ahn Hyung Jin HJ Zamolodchikov Daria D Bhuvanendran Shivaprasad S Fenz Katherine M KM Strickland Sidney S

Neuron 20100601 5

Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the beta-amyloid peptide (Abeta) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Abeta are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravi ...[more]

PMID: 20547128

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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

Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease.

Publications

Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease.

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