Fibrinogen and β-Amyloid Association Alters Thrombosis and Fibrinolysis: A Possible Contributing Factor to Alzheimer's Disease

Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.
Neuron (Impact Factor: 15.05). 06/2010; 66(5):695-709. DOI: 10.1016/j.neuron.2010.05.014
Source: PubMed


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.

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Available from: Daria Zamolodchikov, Oct 13, 2015
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    • "Besides platelet hyper activation, coagulation is also impaired in AD patients. In particular it has been observed that Aβ is able to bind fibrinogen and that fibrin clot formed in the presence of Aβ are more stable and more resistant to degradation during fibrinolysis (Ahn et al., 2010; Cortes-Canteli et al., 2010). After BBB alterations fibrinogen may deposit to brain blood vessel and accumulate in CAA and parenchyma in AD patients, and in AD mouse models (Paul et al., 2007). "
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    ABSTRACT: Alzheimer’s disease (AD) is the most common neurodegenerative cause of dementia in the elderly. AD is accompanied by the accumulation of amyloid peptides in the brain parenchyma and in the cerebral vessels. The sporadic form of AD accounts for about 95% of all cases. It is characterized by a late onset, typically after the age of 65, with a complex and still poorly understood aetiology. Several observations point towards a central role of cerebrovascular dysfunction in the onset of sporadic AD (SAD). According to the “vascular hypothesis”, AD may be initiated by vascular dysfunctions that precede and promote the neurodegenerative process. In accordance to this, AD patients show increased hemorrhagic or ischemic stroke risks. It is now clear that multiple bidirectional connections exist between AD and cerebrovascular disease, and in this new scenario, the effect of amyloid peptides on vascular cells and blood platelets appear to be central to AD. In this review, we analyze the effect of amyloid peptides on vascular function and platelet activation and its contribution to the cerebrovascular pathology associated with AD and the progression of this disease.
    Frontiers in Cellular Neuroscience 03/2015; DOI:10.3389/fncel.2015.00065 · 4.29 Impact Factor
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    • "To assess whether our lead compound could restore Ainduced altered thrombosis and fibrinolysis in vivo, we examined cerebral blood flow and thrombosis in a transgenic mouse model of AD, Tg6799 mice (Oakley et al., 2006), with or without long-term treatment of RU-505. Blood flow and thrombosis were analyzed by a FeCl 3 -induced thrombosis model combined with intravital microscopy (Cortes-Canteli et al., 2010). We administered RU-505 or vehicle (35 mg/kg dose, every other day) to 4-mo-old Tg6799 and WT littermates for 4 mo (analyzed at 8 mo of age). "
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    ABSTRACT: Many Alzheimer's disease (AD) patients suffer from cerebrovascular abnormalities such as altered cerebral blood flow and cerebral microinfarcts. Recently, fibrinogen has been identified as a strong cerebrovascular risk factor in AD, as it specifically binds to β-amyloid (Aβ), thereby altering fibrin clot structure and delaying clot degradation. To determine if the Aβ-fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the Aβ-fibrinogen interaction. RU-505 restored Aβ-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD. Our studies suggest that inhibitors targeting the Aβ-fibrinogen interaction show promise as therapy for treating AD.
    Journal of Experimental Medicine 05/2014; 211(6). DOI:10.1084/jem.20131751 · 12.52 Impact Factor
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    • "APP which includes complement components, are of interest and A aggregations involved complement activation in atherosclerosis and AD [192] [193]. In particular, convergence of the role of apo E in coronary artery disease is possibly related to the interactions of fibrinogen and A to promote fibrin clot formation and vascular abnormalities [194] [195]. "
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    ABSTRACT: It has been estimated that Alzheimer’s disease (AD), the most common form of dementia, will affect approximately 81 million individuals by 2040. To date, the actual cause and cascade of events in the progression of this disease have not been fully determined. Furthermore, there is currently no definitive blood test or simple diagnostic method for AD. Considerable efforts have been put into proteomic approaches to develop a diagnostic blood test, but to date these efforts have not been successful. More recently, there has been a stronger focus on lipidomic studies in the hope of increasing our understanding of the underlying mechanisms leading to AD and developing an AD blood test. It is well known that the strongest genetic risk factor for AD is the ε4 variant of apolipoprotein E (APOE). Evidence suggests that the ApoE protein, a major lipid transporter, plays a key role in the pathogenesis of AD, and its role in both normal and aberrant lipid metabolism warrants further extensive investigation. Here, we review ApoE-lipid interactions, as well as the roles that lipids may play in the pathogenesis of AD.
    Journal of Genetics and Genomics 05/2014; 41(5). DOI:10.1016/j.jgg.2014.04.003 · 3.59 Impact Factor
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