IgG accumulates in inhibitory hippocampal neurons of experimental antiphospholipid syndrome

Thrombin, a key player in thrombogenesis, affects cells in the brain through activation of its receptors. Low levels of thrombin activity are protective while high levels are toxic. We sought to quantify thrombin activity levels and their spatial distribution in brains of mice following reperfusion after ischemic stroke focusing on infarct, peri-infarct and contralateral areas. In order to find out the contribution of brain-derived thrombin, mRNA levels of both prothrombin and factor X were determined. Furthermore, we assessed the effect of thrombin levels that were measured in the ischemic brain on synaptic transmission. We found that in the brains of mice following transient middle cerebral artery occlusion, thrombin activity is elevated throughout the ischemic hemisphere, including in peri-infarct areas (90 AE 33 and 60 AE 18 mU/mL, in the infarct and peri-infarct areas, respectively, compared to 11 AE 3 and 12 AE 5 mU/mL, in the corresponding contralateral areas; mean AE SE; p < 0.05). Brain mRNA levels of prothrombin and, in particular, factor X are up-regulated in the ischemic core. Hippocampal slices treated with thrombin concentrations as found in the ischemic hemisphere show altered synaptic responses. We conclude that high thrombin activity following reperfusion after ischemic stroke may cause synaptic dysfunction.

show abstract

“…Extracellular recordings in hippocampal slices were performed as previously described (Maggio and Segal ; Katzav et al . ; Maggio et al . ).…”

Section: Methodsmentioning

confidence: 99%

“…Extracellular recordings in hippocampal slices were performed as previously described (Maggio and Segal 2012;Katzav et al 2014;Maggio et al 2015). Briefly, mice were rapidly decapitated, and 400 lm horizontal hippocampal slices were used.…”

Section: Electrophysiologymentioning

confidence: 99%

Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus

Bushi

Shimon

Stein

et al. 2015

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…15 However, neutrophils, astrocytes, neurons, and dendritic cells can also be activated by aPL. [16][17][18][19] It is apparent that all the responses observed represent the result of cellular signal transduction induced by aPL, which is the topic of this review.…”

Section: Cell Types Analyzed In Vitromentioning

confidence: 99%

Mechanisms of Cellular Activation in the Antiphospholipid Syndrome

Müller‐Calleja

Lackner

2017

Semin Thromb Hemost

View full text Add to dashboard Cite

It is long known that antiphospholipid antibodies (aPL) induce proinflammatory and procoagulant cellular responses. The underlying signal transduction has been a major focus of research and is the topic of this review. An amazingly heterogeneous panel of signaling pathways has been described and it turns out that at least some of this heterogeneity can be explained by effects of distinct aPL species. On the one hand, there are antibodies against β2-glycoprotein I (β2GPI) which appear to exert their cellular effects only as a complex of β2GPI/anti-β2GPI. Their major targets are low-density lipoprotein-receptor related protein 8 (LRP8), annexin A2 (ANXA2), toll-like receptor 4 (TLR4), and possibly TLR2. The other relevant aPL species are antibodies against cardiolipin which are internalized into endosomes and induce cellular responses via activation of endosomal NADPH-oxidase. Their cell surface target is still unknown. Another important issue relates to the role of complement. It has been shown in vivo that certain pathogenic effects of aPL depend on complement activation, but the exact interplay with the signaling pathways described earlier needs to be elucidated. Thus, while there has been tremendous progress over the past decade, many open questions remain to be answered.

show abstract

“…Katzav et al reported observing antibody-specific behavioural effects in mice injected with aPL; these mice showed hyperactivity, whilst those injected with antiribosomal P (a postulated antibody in neuropsychiatric lupus) exhibited depression-like behaviour (41). Furthermore, mice immunised with b2 GPI were found to have IgG antibodies accumulating in the hippocampal neurons (42), indicating the ability of these antibodies to not only pass the BBB to directly affect the hippocampal neurons but also possibly initiate a downstream cascade of neuroinflammation by involving other immune cells of the brain such as astrocytes. Examination of the brain tissue of the immunised mice revealed thrombotic occlusion of capillaries with mild inflammation (43).…”

Section: Laboratory Criteriamentioning

confidence: 99%

Antiphospholipid antibodies as biomarkers in psychiatry: review of psychiatric manifestations in antiphospholipid syndrome

Rege

Mackworth‐Young

2015

Translational Developmental Psychiatry

View full text Add to dashboard Cite

Antiphospholipid syndrome (APS) has been implicated in a range of neuropsychiatric presentations. However, there is a paucity of systematic studies on APS in psychiatry. This paper reports the clinical manifestations of APS that are relevant to psychiatrists. The aspects of APS pathogenesis, diagnosis, and treatment presented in this paper are based on a literature review. Treatment-resistant and atypical psychiatric illnesses, severe cognitive dysfunction, migraines, transient ischaemic attacks, and thromboembolic episodes, along with characteristic skin manifestations are the common clinical features of this syndrome. Antiphospholipid antibodies (aPL) may have a causal role in the development of some neuropsychiatric conditions. The existing criteria of APS may not apply to psychiatric patients, which may result in the underdiagnosis of APS in psychiatry. There is no evidence-based guidance available for the treatment of APS in patients with psychiatric symptoms. The treatment of APS with antithrombotic agents in case reports has been reported to yield dramatic improvements in complex and treatment-resistant cases. The possibility of a causal role of aPL in high-morbidity conditions, such as psychosis, depression, and dementia, requires the psychiatrist to be vigilant to the occurrence of this syndrome. There is an urgent need to conduct studies that elucidate the role of aPL in psychiatric presentations, identify patient characteristics, and consider whether new criteria with greater applicability in psychiatry are needed.

show abstract

IgG accumulates in inhibitory hippocampal neurons of experimental antiphospholipid syndrome

Cited by 29 publications

References 40 publications

Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus

Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus

Mechanisms of Cellular Activation in the Antiphospholipid Syndrome

Antiphospholipid antibodies as biomarkers in psychiatry: review of psychiatric manifestations in antiphospholipid syndrome

Contact Info

Product

Resources

About