Relevance of N-terminal residues for amyloid-β binding to platelet integrin α IIb β 3 , integrin outside-in signaling and amyloid-β fibril formation

Donner, L; Gremer, Lothar; Ziehm, Tamar; Gertzen, Christoph G. W.; Gohlke, Holger; Willbold, Dieter; Elvers, Margitta

doi:10.1016/j.cellsig.2018.06.015

Cited by 17 publications

(18 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As the mechanisms leading to platelet adhesion to A β 1-42 remain unclear, but previous work suggest a role for integrin α IIb β 3 on the adhesion to A β 1-40 [22, 31], we tested the activation of this integrin using the antibody PAC1 by flow cytometry. These experiments suggested that only A β 1-42 (but not A β 1-40, A β 2535, or scrambled A β 1-42) induced a convincing activation of integrin α IIb β 3 (Figures 6(a)–6(g)).…”

Section: Resultsmentioning

confidence: 99%

Amyloid Peptideβ1-42 Induces IntegrinαIIbβ3 Activation, Platelet Adhesion, and Thrombus Formation in a NADPH Oxidase-Dependent Manner

Abubaker

Vara

Visconte

et al. 2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

The progression of Alzheimer’s dementia is associated with neurovasculature impairment, which includes inflammation, microthromboses, and reduced cerebral blood flow. Here, we investigate the effects ofβamyloid peptides on the function of platelets, the cells driving haemostasis. Amyloid peptideβ1-42 (Aβ1-42), Aβ1-40, and Aβ25-35 were tested in static adhesion experiments, and it was found that platelets preferentially adhere to Aβ1-42 compared to other Aβpeptides. In addition, significant platelet spreading was observed over Aβ1-42, while Aβ1-40, Aβ25-35, and the scAβ1-42 control did not seem to induce any platelet spreading, which suggested that only Aβ1-42 activates platelet signalling in our experimental conditions. Aβ1-42 also induced significant platelet adhesion and thrombus formation in whole blood under venous flow condition, while other Aβpeptides did not. The molecular mechanism of Aβ1-42 was investigated by flow cytometry, which revealed that this peptide induces a significant activation of integrinαIIbβ3, but does not induce platelet degranulation (as measured by P-selectin membrane translocation). Finally, Aβ1-42 treatment of human platelets led to detectable levels of protein kinase C (PKC) activation and tyrosine phosphorylation, which are hallmarks of platelet signalling. Interestingly, the NADPH oxidase (NOX) inhibitor VAS2870 completely abolished Aβ1-42-dependent platelet adhesion in static conditions, thrombus formation in physiological flow conditions, integrinαIIbβ3 activation, and tyrosine- and PKC-dependent platelet signalling. In summary, this study highlights the importance of NOXs in the activation of platelets in response to amyloid peptideβ1-42. The molecular mechanisms described in this manuscript may play an important role in the neurovascular impairment observed in Alzheimer’s patients.

show abstract

Section: Resultsmentioning

confidence: 99%

Amyloid Peptideβ1-42 Induces IntegrinαIIbβ3 Activation, Platelet Adhesion, and Thrombus Formation in a NADPH Oxidase-Dependent Manner

Abubaker

Vara

Visconte

et al. 2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…Previous studies have suggested that aggregated platelets release Aβ, as well as ADP and clusterin, which promote Aβ aggregation. 27 Furthermore, a previous study comparing plasma and serum Aβ levels reported approximately twofold increases in Aβ levels in serum samples, compared with plasma samples. 28 The relationship between clusterin and Aβ aggregation might have a particular impact on Aβ oligomer levels.…”

Section: Discussionmentioning

confidence: 95%

Serum levels and mutual correlations of amyloid β in patients with depression

Yasuda

Baba

Maeshima

et al. 2019

Geriatrics Gerontology Int

View full text Add to dashboard Cite

Aim: Epidemiological studies have shown that depression is a risk factor for Alzheimer's disease (AD). Although the biological mechanism underlying the link between depression and AD is unclear, altered amyloid β (Aβ) metabolism in patients with depression has been suggested as a potential mechanism. Results from previous studies of Aβ metabolism in patients with depression have been inconsistent, and Aβ polymerization, which is a crucial process in AD pathology, has not previously been assessed.Methods: Serum levels of Aβ40, Aβ42 and Aβ oligomers were evaluated in 104 inpatients with major depressive disorder (MDD) and 132 healthy control individuals.Results: Lower serum Aβ42 levels were observed in patients with MDD, but there was no difference in serum Aβ oligomer levels between the MDD group and the healthy control group, even in older adults. Interestingly, serum Aβ oligomer levels in patients with MDD were dependent on serum Aβ42 levels, regardless of age, and this relationship was not observed in the control group.Conclusions: These results suggest that Aβ42 is more prone to aggregation and polymerization in patients with depression than in healthy individuals, suggesting a possible mechanism underlying the transition from depression to AD. Geriatr Gerontol Int 2020; 20: 125-129.

show abstract

“…Data from WASP −/− mice showed that integrin αIIbβ3 outside-in signaling, such as fibrinogen and JON/A binding under agonist stimulation, is normal, whereas integrin αIIbβ3 outside-in signaling-dependent events, such as spreading on immobilized fibrinogen, fibrin clot retraction, and rebleeding, are impaired [180]. Some extracellular materials, pathogens, and other factors, such as amyloid-β [185], UV [186], Mucor circinelloides [187], heparin [188], and hypoxia [189], also regulate αIIbβ3 signaling. Peroxisome proliferator-activated receptor γ (PPARγ) [190], reelin [191, 192], and disulfide isomerase [193] were also reported to be involved in integrin αIIbβ3 outside-in signaling.…”

Section: Integrin αIibβ3 Outside-in Signalingmentioning

confidence: 99%

Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting

et al. 2019

View full text Add to dashboard Cite

Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low-to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.

show abstract

Relevance of N-terminal residues for amyloid-β binding to platelet integrin α IIb β 3 , integrin outside-in signaling and amyloid-β fibril formation

Cited by 17 publications

References 44 publications

Amyloid Peptideβ1-42 Induces IntegrinαIIbβ3 Activation, Platelet Adhesion, and Thrombus Formation in a NADPH Oxidase-Dependent Manner

Amyloid Peptideβ1-42 Induces IntegrinαIIbβ3 Activation, Platelet Adhesion, and Thrombus Formation in a NADPH Oxidase-Dependent Manner

Serum levels and mutual correlations of amyloid β in patients with depression

Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting

Contact Info

Product

Resources

About