Biology subjects

Elvers, M.

Publications and source records attributed to Elvers, M..

11 recordsLinked to original sources

bioRxiv2026

Dysregulated Platelet GPIb alpha - VWF Signalling in Abdominal Aortic Aneurysm formation and Progression

Background: Platelets are critical drivers of thrombo-inflammatory responses in different cardiovascular diseases. Abdominal aortic aneurysm (AAA) is a progressive, life-threatening vascular disorder mainly characterised by chronic inflammation, extracellular matrix degradation, and the formation of a platelet-rich intraluminal thrombus (ILT). Experimental and clinical evidence identified platelets as main players in AAA pathology as evidenced by elevated platelet activation and procoagulant activity that critically contribute to AAA progression. Methods: The present study investigated the contribution of glycoprotein (GP)Ib alpha, the von Willebrand factor (VWF)-binding subunit of the platelet GPIb-IX-V complex, to AAA initiation and progression in experimental AAA using the ePPE mouse model and in patients. Results: Genetic ablation of platelet GPIb alpha significantly attenuated early aneurysm expansion in experimental AAA, indicating a critical role for GPIb alpha during the initial stages of aneurysm development. This initial effect was compensated at later time points showing no differences in aneurysm progression between groups. Notably, genetic deletion of GPIb alpha induced a constitutively hyperactive platelet phenotype already in naive mice that was further amplified during experimental AAA. This elevated platelet hyperactivity was mainly due to increased GPVI activation of platelets 28 days post-surgery. To assess the clinical relevance, spatial profiles of human ILT specimens from patients with AAA were analysed. In the ILT, we detected a highly compartmentalised distribution of GPIb alpha and VWF with pronounced enrichment within the luminal layer. In parallel, circulating VWF activity as well as platelet surface expression of GPIb alpha were significantly increased in patients with AAA. Conclusion: Collectively, these findings identify a dysregulated GPIb alpha-VWF axis in human AAA pathology, mainly characterised by enhanced platelet GPIb alpha surface expression and increased activity of circulating VWF.

pathology↗

bioRxiv2026

The heart-liver axis controls platelet turnover by hepatic STAT3 phosphorylation and TPO regulation after acute myocardial infarction

Background: Platelets play a critical role in thrombo-inflammation following acute myocardial infarction (AMI). Objectives: Their impact on hepatic thrombopoietin (TPO) regulation after AMI remains poorly understood to date. Methods: Wildtype, thrombocytopenic or GPVI deficient mice underwent ischemia/reperfusion (I/R) injury. Platelet activation and turnover, and hepatic expression of different receptors involved in TPO regulation were analyzed. Results: Here, we identify a heart-liver axis that dynamically regulates platelet production post AMI. An elevated platelet turnover with increased reticulated as well as desialylated platelets early after AMI was detected. This was accompanied by the upregulation of specific receptors such as Asgr1/2 and IL-6R and increased phosphorylation of STAT3 in the liver and elevated numbers of megakaryocytes in spleen tissue. Consequently, increased TPO plasma levels at 24h post AMI were detected and platelet counts were rapidly restored after AMI. Platelet depletion induces a compensatory increase in hepatic TPO expression and plasma TPO levels, accompanied by dysregulated STAT3 signaling. This response contrasts with GPVI-deficient (Gp6-/-) mice, which exhibit no major alterations in TPO regulation, suggesting distinct mechanisms between acute thrombocytopenia and chronic platelet receptor deficiency in platelet homeostasis after AMI. These findings provide the first evidence of a direct heart-liver axis regulating platelet homeostasis after AMI, driven by inflammatory and hepatic signaling pathways. Conclusions: Our study highlights a previously unrecognized role of the heart-liver axis in controlling platelet turnover, with hepatic STAT3 signaling as a key mediator. These insights enhance our understanding of post AMI platelet homeostasis and may be critical for future therapeutic strategies.

molecular biology↗

bioRxiv2025

Elevated IL-1 beta plasma levels, altered platelet activation and cardiac remodeling lead to moderately decreased LV function in Alzheimer transgenic mice after myocardial ischemia and reperfusion

IntroductionNeurodegeneration and dementia are key factors in Alzheimers disease (AD). The deposition of amyloid-{beta} into senile plaques in the brain parenchyma and in cerebral vessels known as cerebral amyloid angiopathy (CAA) are the main clinical parameters of AD. Acute myocardial infarction (AMI) and AD share a comparable pathophysiology. In detail, AMI survivors have a higher risk of vascular dementia and AD patients with AMI face a poor prognosis with a high rate of major adverse cardiovascular events. High blood levels of amyloid-{beta}40 are identified in patients with high risk for cardiovascular death. However, the underlying mechanisms and the consequences of AMI in AD patients are unclear to date. MethodsAD transgenic APP23 mice were analysed in an experimental AMI using the closed-chest model. ResultsAPP23 mice displayed significantly decreased left ventricular function as detected by FS/MPI (fractional shortening/myocardial performance index) after 24 h and 3 weeks after ligation of the LAD compared to WT controls. No differences have been observed in infarct and scar size. However, the analysis of cardiac remodeling after 3 weeks showed an altered composition of the collagen tissue of the scar with elevated tight but reduced fine collagen in APP23 mice. Altered scar formation was accompanied by elevated degranulation of platelets following activation of the collagen receptor GPVI. ConclusionThe here presented results suggest that AD patients are at higher risk for cardiac damage after AMI that might increase the risk for cardiovascular death. This implies the need of a personalized therapy of AMI in AD patients.

neuroscience↗

bioRxiv2025

Platelets from early-stage Alzheimer patients show enhanced amyloid binding, an elevated open canalicular system and sex-specific differences in their activation profile

IntroductionAlzheimers disease (AD) is associated with neurodegeneration and dementia. The clinical parameters include the deposition of amyloid-{beta} into senile plaques in the brain parenchyma and in cerebral vessels known as cerebral amyloid angiopathy (CAA). Currently, {beta}-amyloid-antibodies are emerging as possible therapy for AD. Several biomarkers, such as {beta}-Amyloid and tau-protein have gained significant value for diagnosing early AD. However, these biomarkers require cerebrospinal fluid. Blood tests for screening of AD are urgently needed. MethodsPatients diagnosed with early AD were analyzed for extracellular amyloid-{beta} binding to platelets, platelet morphology and platelet activation and compared to age-matched controls. ResultsBeside unaltered platelet number and size, we detected increased binding of amyloid-{beta} to activated platelets isolated from AD patients. Electron microscopy revealed an altered platelet morphology in AD patients including the number of dense granules and the area of the open canalicular system (OCS) as compared to controls. While only minor differences in platelet activation were detected between patients and controls, a significant reduction of integrin IIb{beta}3 (fibrinogen receptor) activation was evident in platelets from female compared to male AD patients as determined by flow cytometry. ConclusionThe here presented results emphasize the importance to increase our understanding how platelets contribute to AD pathology in patients in a sex-specific manner. Furthermore, platelet parameters might serve as an ideal biomarker for a first prognosis of AD because platelets can be easily accessed by blood samples. These parameters might include a sex-specific platelet activation profile, the capability to bind A{beta} to the platelet surface and the dimension of the OCS by electron microscopy.

neuroscience↗

bioRxiv2025

Long-term antiplatelet therapy protects against cerebral but not parenchymal amyloid plaque formation and neurodegeneration in transgenic mice of Alzheimers disease

IntroductionCerebral amyloid angiopathy (CAA) is characterized by the aggregation of amyloid-{beta} peptides in cerebral blood vessels, leading to a loss of vascular integrity and contributing to the progression of Alzheimers disease (AD). In our previous study, we showed that short-term treatment with the antiplatelet drug clopidogrel, a P2Y12 inhibitor that irreversibly blocks ADP signaling, reduced the incidence of CAA in the APP23 mouse model of Alzheimers disease providing strong evidence for platelets to contribute to AD pathology. The objective of the present study was to ascertain whether long-term treatment with clopidogrel and the earlier initiation of treatment prior to the formation of A{beta} deposits prevents pathological changes associated with Alzheimers disease. MethodsAPP23 mice were treated with clopidogrel for 15 month and analyzed for AD pathology. ResultsWe detected increased permeability of the blood brain barrier in different brains regions of APP23 mice. Moreover, platelets migrated into the brain parenchyma and accumulated around amyloid plaques in the brain of APP23 mice. Although we detected platelets in close proximity to microglia and neurons in the cortex and hippocampus of APP23 mice, we did not observe any differences in neurodegeneration or gliosis in Clopidogrel treated APP23 mice. Furthermore, pathological analysis showed a significant reduction in CAA and in soluble A{beta}42 levels in the brain of Clopidogrel versus placebo treated APP23 mice but no differences in plaque load in the brain parenchyma. ConclusionThus, antiplatelet therapy may alleviate amyloid pathology in cerebral vessels leading to improved blood perfusion in AD patients.

pathology↗

bioRxiv2024

Platelets induce cell apoptosis of cardiac cells via FasL after acute myocardial infarction

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Cell apoptosis in the myocardium plays an important role in ischemia and reperfusion (I/R) injury, leading to cardiac damage and dysfunction. Platelets are major players of hemostasis and play a crucial role in vessel occlusion, inflammation and cardiac remodeling after I/R. Here, we studied the impact of platelets on cell apoptosis in the myocardium using a close-chest mouse model of AMI. We found caspase-3 positive resident cardiac cells while leukocytes were negative for caspase-3. Using two different mouse models of thrombocytopenia, we detected a significant reduction of caspase-3 positive cells in the infarct border zone after I/R injury. Further, we identified platelet FasL to induce cell apoptosis via the extrinsic pathway of Fas receptor activation of target cells. Mechanistically, hypoxia triggers platelet adhesion to FasR suggesting that platelet induced apoptosis is elevated after I/R. Platelet-specific FasL knock-out mice showed reduced Bax and BcL-2 expression suggesting that platelets modulate the intrinsic and the extrinsic pathway of apoptosis leading to reduced infarct size after myocardial I/R injury. Therefore, platelet induced cardiac damage needs to be taken into account while optimizing antithrombotic/antiplatelet strategies for patients with AMI.

molecular biology↗

bioRxiv2024

Crosstalk between thrombospondin-1 and CD36 modulates platelet-RBC interaction limiting thrombosis and abdominal aneurysm formation

Red blood cells (RBCs) contribute to hemostasis and thrombosis by interaction with platelets via the FasL-FasR pathway to induce procoagulant activity and thrombin formation. Here, we identified a novel mechanism of platelet-RBC interaction via the CD36-thrombospondin-1 (TSP-1) signaling pathway, which is important in thrombus formation and the recruitment of RBCs to collagen-adherent platelets. Platelet-released TSP-1 can bind to CD36 at the RBC membrane to enhance procoagulant activity and to increase the activation of integrin IIb{beta}3, which represents an additional ligand for erythroid FasR, suggesting that both mechanisms of platelet-RBC interaction act in concert to propagate thrombus formation. In patients with abdominal aortic aneurysm (AAA), enhanced procoagulant activity of RBCs and platelets is accompanied by elevated exposure of TSP-1 and FasL at the platelet surface and accumulation of TSP-1 in the aortic wall and the intraluminal thrombus, suggesting that platelet-RBC interaction plays an important role in AAA pathology. TSP-1-deficient mice are protected against aortic diameter expansion in an experimental model of AAA, highlighting the crucial role of the CD36-TSP-1 axis in AAA. Thus, interfering with platelet-RBC interaction may be a promising therapeutic approach to reduce pro-coagulant activity and preserve AAA patients from surgery or rupture.

pathology↗

bioRxiv2023

Collagen receptor GPVI-mediated platelet activation and pro-coagulant activity aggravates inflammation and aortic wall remodelling in abdominal aortic aneurysm

Platelets play an important role in cardio- and cerebrovascular diseases. Abdominal aortic aneurysm (AAA) is a highly lethal, atherosclerotic-related disease with characteristic features of progressive dilatation of the abdominal aorta and degradation of the vessel wall accompanied by chronic inflammation. Platelet activation and pro-coagulant activity play a decisive role in the AAA pathology as they might trigger AAA development in both mice and men. The present study investigated the impact of the major platelet collagen receptor glycoprotein (GP)VI in cellular processes underlying AAA initiation and progression. Genetic deletion of GPVI offered protection of mice against aortic diameter expansion in experimental AAA. Mechanistically, GPVI deficiency resulted in decreased inflammation with reduced infiltration of neutrophils and platelets into the aortic wall. Further, remodelling of the aortic wall was improved in absence of GPVI, indicated by reduced MMP2/9 and OPN plasma levels and an enhanced -SMA content within the aortic wall, accompanied by reduced cell apoptosis. As a result, an elevation in intima/media thickness and elastin content were observed in GPVI-deficient PPE mice, coursing a significantly reduced aortic diameter expansion and reduced aneurysm incidence. In AAA patients, enhanced plasma levels of soluble GPVI and fibrin, besides fibrin accumulation within the intraluminal thrombus (ILT) suggested that GPVI might serve as a biomarker and mediator in fibrin-supported stabilization of the ILT. In conclusion, our results emphasize the potential need for a GPVI-targeted anti-platelet therapy to reduce AAA initiation and progression, as well as to protect AAA patients from aortic rupture. Translational perspectiveAbdominal aortic aneurysm (AAA) is an atherosclerotic-related, cardiovascular disease (CVD) with high mortality. The impact of platelets in different cellular processes underlying AAA initiation and progression remains unclear.Therefore, we analysed the role of the major platelet collagen receptor GPVI in the pathogenesis of AAA. Results from platelet depleted mice and patients with AAA revealed a significant contribution of GPVI to the inflammatory response and remodelling process of the aorta. Further, elevated accumulation of fibrin, a recently identified ligand of GPVI in the intraluminal thrombus (ILT) and in the plasma of AAA patients, suggests that GPVI binding to fibrin plays a role in ILT formation and probably stabilization of the abdominal aorta. Furthermore, increased levels of sGPVI suggest that GPVI might serve as a clinical biomarker for AAA. Thus, therapeutic targeting of GPVI-mediated platelet activation might be an effective anti-thrombotic strategy for AAA patients.

cell biology↗

bioRxiv2023

Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer's Disease Mouse Models

The development of novel drugs for Alzheimers disease has proven difficult, with a high failure rate in clinical trials. Typically, transgenic mice displaying amyloid-{beta} peptide brain pathology are used to develop therapeutic options and to test their efficacy in preclinical studies. However, the properties of A{beta} in such mice have not been systematically compared to A{beta} from the patient brains. Here, we determined the structures of nine ex vivo A{beta} fibrils from six different mouse models by cryo-EM. We found novel A{beta} fibril structures in the APP/PS1, ARTE10, and tg-SwDI models, whereas the human familial type II fibril fold was found in the ARTE10, tg-APPSwe, and APP23 models. The tg-APPArcSwe mice showed an A{beta} fibril whose structure resembles the human sporadic type I fibril. These structural elucidations are key to the selection of adequate mouse models for the development of novel plaque-targeting therapeutics and PET imaging tracers. One Sentence SummaryCryo-EM structures of A{beta} fibrils extracted from brains of mouse models used for Alzheimers disease preclinical research are presented.

neuroscience↗

bioRxiv2022

Platelets modulate inflammation and matrix remodeling in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a highly lethal disease with progressive dilatation of the abdominal aorta accompanied by degradation and remodelling of the vessel wall due to chronic inflammation. Platelets play an important role in cardiovascular diseases but their role in AAA is poorly understood. The present study revealed that platelets play a crucial role in promoting AAA through modulation of inflammation and degradation of the ECM. They are responsible for the up-regulation of SPP1 (osteopontin, OPN) gene expression in macrophages and aortic tissue, which triggers inflammation and remodeling but also platelet adhesion and migration into the abdominal aortic wall and the intraluminal thrombus (ILT). Further, enhanced platelet activation and pro-coagulant activity results in elevated gene expression of various cytokines, Mmp9 and Col1a1 in macrophages and Il-6 and Mmp9 in fibroblasts. Enhanced platelet activation and pro-coagulant activity was also detected in AAA patients. Further, we detected platelets and OPN in the vessel wall and in the ILT of patients who underwent open repair of AAA. Platelet depletion in experimental murine AAA reduced inflammation and ECM remodeling, with reduced elastin fragmentation and aortic diameter expansion. Of note, OPN co-localized with platelets, suggesting a potential role of OPN for the recruitment of platelets into the ILT and the aortic wall. In conclusion, our data strongly supports the potential relevance of anti-platelet therapy to reduce AAA progression and rupture in AAA patients. Translational perspectiveAbdominal aortic aneurysm (AAA) is a severe cardiovascular disease (CVD) with high mortality. Since the role of platelets is unclear, we explored platelet-mediated processes in the pathogenesis of AAA. Results from platelet depleted mice and patients with AAA revealed that platelets modulate inflammatory and stiffness-related gene expression of macrophages and fibroblasts. Further, platelets induce the release of osteopontin important for the recruitment of platelets to the aortic wall and to the intraluminal thrombus (ILT). Consequently, platelet depletion significantly reduced aneurysm growth. Thus, therapeutic targeting of platelet activation might be crucial for the treatment of patients to reduce AAA formation and progression.

molecular biology↗

bioRxiv2022

Platelet pannexin-1 channels modulate inflammation during abdominal aortic aneurysm formation

Abdominal aortic aneurysm (AAA) is a common disease and highly lethal if untreated. The progressive dilatation of the abdominal aorta is accompanied by degradation and remodeling of the vessel wall due to chronic inflammation. Pannexins represent anion-selective channels and play a crucial role in non-vesicular ATP release to amplify paracrine signaling in cells. Thus, pannexins are involved in many (patho-) physiological processes. Recently, Panx1 channels were identified to be significantly involved in AAA formation through endothelial derived Panx1 regulated inflammation and aortic remodeling. In platelets, Panx1 becomes activated following activation of glycoprotein (GP)VI. Since platelets play a role in cardiovascular diseases including AAA, we analyzed the contribution of platelet Panx1 in the progression of AAA. We detected enhanced Panx1 plasma levels in AAA patients. In experimental AAA using the pancreatic porcine elastase (PPE) mouse model, a major contribution of platelet Panx1 channels in platelet activation, pro-coagulant activity of platelets and platelet-mediated inflammation has been detected. In detail, platelets are important for the migration of neutrophils into the aortic wall induced by direct cell interaction and by activation of endothelial cells. Decreased platelet activation and inflammation did not affect ECM remodeling or wall thickness in platelet-specific Panx1 knock-out mice following PPE surgery. Thus, aortic diameter expansion at different time points after elastase infusion of the aortic wall was unaltered in platelet-specific Panx1 deficient mice suggesting that the modulation of inflammation alone does not affect AAA formation and progression. In conclusion, our data strongly supports the role of platelets in inflammatory responses in AAA via Panx1 channels and adds important knowledge about the significance of platelets in AAA pathology important for the establishment of an anti-platelet therapy for AAA patients.

cell biology↗