Amyloid Precursor Protein and Amyloid β Peptide in Human Platelets

Skovronsky, Daniel; Lee, Virginia M.‐Y.; Praticò, Domenico

doi:10.1074/jbc.m006285200

Cited by 108 publications

(75 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Platelets contribute to >90% amyloid precursor protein in circulation (44), which, upon proteolytic cleavage by β-and γ-secretases, yields Aβ 40 (45). Despite low plasma levels, high local concentrations of Aβ are achieved (28) at the site of thrombus formation owing to release from stimulated platelets (46,47) and at the sites of CAA (48) or atherosclerotic plaques (49,50), which can initiate vicious cycles of platelet stimulation and Aβ release and potentially lead to massive thrombosis. Based on observations presented in this study, it is tempting to speculate that fibrinogen acts as a physiological "shield" to preclude Aβ-induced activation of platelets, thus keeping the prothrombotic attributes of amyloid peptide strictly under check and providing steady protection against thrombotic vascular occlusion.…”

Section: Discussionmentioning

confidence: 99%

Plasma Fibrinogen Is a Natural Deterrent to Amyloid β-Induced Platelet Activation and Neuronal Toxicity

Sonkar

Kulkarni

Chaurasia

et al. 2016

Mol Med

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by extensive loss of neurons and deposition of amyloid β (Aβ) in the form of extracellular plaques. Aβ is considered to have a critical role in synaptic loss and neuronal death underlying cognitive decline. Platelets contribute to 95% of circulating amyloid precursor protein that releases Aβ into circulation. We have recently demonstrated that the Aβ active fragment containing amino acid sequence 25-35 (Aβ [25][26][27][28][29][30][31][32][33][34][35] ) is highly thrombogenic in nature and elicits strong aggregation of washed human platelets in a RhoA-dependent manner. In this study, we evaluated the influence of fibrinogen on Aβ-induced platelet activation. Intriguingly, Aβ failed to induce aggregation of platelets suspended in plasma but not in buffer. Fibrinogen brought about dose-dependent decline in aggregatory response of washed human platelets elicited by Aβ [25][26][27][28][29][30][31][32][33][34][35] , which could be reversed by increasing doses of Aβ. Fibrinogen also attenuated Aβ-induced platelet responses such as secretion, clot retraction, rise in cytosolic Ca +2 and reactive oxygen species. Fibrinogen prevented intracellular accumulation of full-length Aβ peptide (Aβ 42 ) in platelets as well as neuronal cells. We conclude that fibrinogen serves as a physiological check against the adverse effects of Aβ by preventing its interaction with cells. online address: http://www.molmed.org

show abstract

Section: Discussionmentioning

confidence: 99%

Plasma Fibrinogen Is a Natural Deterrent to Amyloid β-Induced Platelet Activation and Neuronal Toxicity

Sonkar

Kulkarni

Chaurasia

et al. 2016

Mol Med

View full text Add to dashboard Cite

show abstract

“…on May 9, 2018. by guest www.bloodjournal.org From formation [32][33][34] and to the clearance of A␤ from CAA vessels into the circulation by LRP receptors (reviewed by Deane et al 35 ). Furthermore, fibrinogen escaping the AD vasculature through a leaky blood-brain barrier 36 can encounter high concentrations of A␤ in the brain parenchyma, resulting in persistent fibrin deposits.…”

mentioning

confidence: 99%

Aβ delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin

Zamolodchikov

Strickland

2012

Blood

157

View full text Add to dashboard Cite

Alzheimer disease is characterized by the presence of increased levels of the ␤-amyloid peptide (A␤) in the brain parenchyma and cerebral blood vessels. This accumulated A␤ can bind to fibrin(ogen) and render fibrin clots more resistant to degradation. Here, we demonstrate that A␤ 42 specifically binds to fibrin and induces a tighter fibrin network characterized by thinner fibers and increased resistance to lysis. However, A␤ 42 -induced structural changes cannot be the sole mechanism of delayed lysis because A␤ overlaid on normal preformed clots also binds to fibrin and delays lysis without altering clot structure. In this regard, we show that A␤ interferes with the binding of plasminogen to fibrin, which could impair plasmin generation and fibrin degradation. Indeed, plasmin generation by tissue plasminogen activator (tPA), but not streptokinase, is slowed in fibrin clots containing A␤ 42 , and clot lysis by plasmin, but not trypsin, is IntroductionCerebrovascular dysfunction has been implicated as an early event in Alzheimer disease (AD) progression, 1-4 but the origins and mechanisms of vascular dysfunction in AD are not clear. The ␤-amyloid peptide (A␤) accumulates in the brain parenchyma and blood vessel walls of AD patients and has been genetically and clinically linked to AD. We have previously shown that fibrinogen, the main protein component of blood clots, can bind A␤ 42 (henceforth designated A␤) specifically with a K d of 26.3 Ϯ 6.7nM. 5 We also found that fibrin clots formed in the presence of A␤ are structurally altered and more resistant to fibrinolysis than normal clots. 6 However, the mechanism by which A␤-fibrin(ogen) binding delays fibrin clot lysis has not been defined.Fibrin clot lysis is mediated by plasmin, a serine protease that cleaves the fibrin network at specific sites. Plasmin is derived from plasminogen by tissue plasminogen activator (tPA) in the presence of fibrin, which itself enhances the rate of the reaction. One fibrin site initially involved in plasminogen activation by tPA includes residues 148-160 on the A␣-chain (reviewed by Medved and Nieuwewnhuizen 7 ). This site becomes exposed and available for plasminogen binding after the conversion of fibrinogen to fibrin, 8 but could remain hidden if clots are formed in the presence of A␤, leading to delayed clot lysis. This hypothesis is derived from our finding that A␤ binds the fibrinogen ␤-chain near the ␤-hole, 5 which is in close spatial proximity to residues 148-160 of the A␣-chain. 9 Another potential explanation for delayed clot lysis is based on the relationship between fibrin structure and its susceptibility to fibrinolysis. Tighter fibrin networks composed of thin fibers are degraded less efficiently by plasmin than those composed of thick fibers 10-13 because: (1) there are more fibers to be cleaved, 11,14 requiring plasmin to detach from and move between fibers more frequently 15 ; and (2) decreased network porosity of tighter fibrin networks results in impeded diffusion of fibrinolytic enzymes throughout the clot (...

show abstract

“…Um estudo, a fim de determinar o efeito do ácido acetilsalicílico (inibidor não-seletivo da COX) sobre a agregação da Aβ e sobre a produção de APP, demonstrou que essa droga não foi capaz de modificar os níveis de Aβ e APP no soro e no plasma 56 , sugerindo que a COX não exerceu um papel importante na secreção de APP.…”

Section: A Doença De Alzheimer E Os Antiinflamatóriosunclassified

A doença de Alzheimer: aspectos fisiopatológicos e farmacológicos

Sereniki¹,

Vital

2008

Rev. psiquiatr. Rio Gd. Sul

114

View full text Add to dashboard Cite

Endereço para correspondênciaRev Psiquiatr RS. 2008;30(1 Supl). RESUMOA doença de Alzheimer é a patologia neurodegenerativa mais freqüente associada à idade, cujas manifestações cognitivas e neuropsiquiátricas resultam em deficiência progressiva e incapacitação. A doença afeta aproximadamente 10% dos indivíduos com idade superior a 65 anos e 40% acima de 80 anos. Estima-se que, em 2050, mais de 25% da população mundial será idosa, aumentando, assim, a prevalência da doença. O sintoma inicial da doença é caracterizado pela perda progressiva da memória recente. Com a evolução da patologia, outras alterações ocorrem na memória e na cognição, entre elas as deficiências de linguagem e nas funções vísuo-espaciais. Esses sintomas são freqüentemente acompanhados por distúrbios comportamentais, incluindo agressividade, depressão e alucinações. O objetivo deste trabalho foi revisar, na literatura médica, os principais aspectos que envolvem a doença de Alzheimer, como as características histopatológicas, a neuroinflamação e a farmacoterapia atual.Descritores: Doença de Alzheimer, inflamação, acetilcolinesterase, inibidores de ciclooxigenase. ABSTRACTAlzheimer's disease is the most frequent age-associated neurodegenerative disease. Its

show abstract

Amyloid Precursor Protein and Amyloid β Peptide in Human Platelets

Cited by 108 publications

References 31 publications

Plasma Fibrinogen Is a Natural Deterrent to Amyloid β-Induced Platelet Activation and Neuronal Toxicity

Plasma Fibrinogen Is a Natural Deterrent to Amyloid β-Induced Platelet Activation and Neuronal Toxicity

Aβ delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin

A doença de Alzheimer: aspectos fisiopatológicos e farmacológicos

Contact Info

Product

Resources

About