Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy

Wyatt, Season K.; Witt, Thomas C.; Barbaro, Nicholas M.; Cohen-Gadol, Aaron; Brewster, Amy L.

doi:10.1016/j.expneurol.2017.06.009

Cited by 66 publications

(77 citation statements)

References 42 publications

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“…Furthermore, genetic deficiency of C3 or C3aR mitigated microglial-dependent synaptic loss and cognitive impairment in a murine model of neuroinvasive West Nile virus infection 65 . Importantly, enrichment of C1q and C3 in the cortex of patients with refractory epilepsy correlated with markers of aberrant microglial activity, suggesting that complement-driven loss of inhibitory synapses might account for the neuronal hyperexcitability observed in human epilepsy 66 .…”

Section: Complement In Inflammatory Diseasesmentioning

confidence: 97%

Novel mechanisms and functions of complement

et al. 2017

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Progress in the beginning of the 21st century transformed our perception of complement from a blood-based antimicrobial system to a global regulator of immunity and tissue homeostasis. More recent years have witnessed remarkable advances regarding structure-function insights, mechanisms and locations of complement activation, thereby adding new layers of complexity in the biology of complement. This complexity is readily reflected by the multifaceted and contextual involvement of complement-driven networks in a wide range of inflammatory and neurodegenerative disorders and cancer. This Review provides an updated view of new and previously unanticipated functions of complement and how these impact immunity and disease pathogenesis.

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Section: Complement In Inflammatory Diseasesmentioning

confidence: 97%

Novel mechanisms and functions of complement

et al. 2017

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“…Complement has also been implicated in microglial elimination of synapses in AD, mediating pathological loss of synapses in AD mouse models (Hong et al, 2016;Shi et al, 2017). Complement is also involved in synaptic loss in response to acute brain injury (Alawieh, Langley, Weber, Adkins, & Tomlinson, 2018;Norris et al, 2018), chronic tau accumulation (Dejanovic et al, 2018), epilepsy (Wyatt, Witt, Barbaro, Cohen-Gadol, & Brewster, 2017), neuroinflammation (Watkins et al, 2016), and other disease contexts (Sekar et al, 2016). Other microglial signaling components also have important functions in both brain development and neurodegeneration, including CX3CR1 (Basilico et al, 2019;Paolicelli et al, 2011;Sheridan & Murphy, 2013) and progranulin (Baker et al, 2006;Lui et al, 2016), further illustrating that common mechanisms can mediate important microglial functions in brain health and disease (Tenner, Stevens, & Woodruff, 2018).…”

Section: Introductionmentioning

confidence: 99%

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Jay

Saucken

Muñoz

et al. 2019

Glia

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Variants in the microglial receptor TREM2 confer risk for multiple neurodegenerative diseases. However, it remains unknown how this receptor functions on microglia to modulate these diverse neuropathologies. To understand the role of TREM2 on microglia more generally, we investigated changes in microglial function in Trem2−/− mice. We found that loss of TREM2 impairs normal neurodevelopment, resulting in reduced synapse number across the cortex and hippocampus in 1‐month‐old mice. This reduction in synapse number was not due directly to alterations in interactions between microglia and synapses. Rather, TREM2 was required for microglia to limit synaptic engulfment by astrocytes during development. While these changes were largely normalized later in adulthood, high fat diet administration was sufficient to reinitiate TREM2‐dependent modulation of synapse loss. Together, this identifies a novel role for microglia in instructing synaptic pruning by astrocytes to broadly regulate appropriate synaptic refinement, and suggests novel candidate mechanisms for how TREM2 and microglia could influence synaptic loss in brain injury and disease.

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“…Eleven complement analytes were selected for this study, guided by reference to previous studies of complement biomarkers in epilepsy which have described increased serum levels or gene expression of C3, C4, C1q, iC3b and terminal complement complex (TCC), and availability of reagents and in-house assays [23,24,26,28,30]. The concentrations of nine analytes: iC3b, C1q, C3, C4, Properdin, Factor B (FB), Factor H (FH), C1 inhibitor (C1inh), and TCC were measured using established in-house enzyme-linked immunosorbent assays (ELISA) ( Table 2).…”

Section: Immunoassaysmentioning

confidence: 99%

Complement system biomarkers in epilepsy

Kopczynska

Zelek

Vespa

et al. 2018

Seizure

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Purpose: To explore whether complement dysregulation occurs in a routinely recruited clinical cohort of epilepsy patients, and whether complement biomarkers have potential to be used as markers of disease severity and seizure control. analysis were used to test whether combinations of complement analytes were predictive of epilepsy diagnoses and seizure occurrence. Correlation between number and type of antiepileptic drugs (AED) and complement analytes was also performed. Methods Results:We found: 1) significant differences between all epilepsy patients and controls for TCC (p˂ 0.01) and FH (p˂ 0.01) after performing univariate analysis.2) multivariate analysis combining six analytes (C3, C4, Properdin, FH, C1Inh, Clu) to give a predictive value (area under the curve) of 0.80 for differentiating epilepsy from controls.3) significant differences in complement levels between patients with controlled seizures (n=65) in comparison with uncontrolled seizures (n=87). Levels of iC3b, Properdin and Clu were decreased and levels of C4 were increased in patients with uncontrolled seizures. 4) no correlation was found between the level of complement biomarkers and the number of AEDs taken, but an association between some analyte levels and drug therapy was seen in patients taking sodium valproate, clobazam, and perampanel. Complement biomarkers in EpilepsyPage 3 Conclusion: This study adds to evidence implicating complement in pathogenesis of epilepsy and may allow the development of better therapeutics and prognostic markers in the future.Replication in a larger sample set is needed to validate the findings of the study. Highlights:• Plasma complement biomarkers distinguish epilepsy patients from controls (area under the curve: 0.8).• Plasma complement biomarkers differ between controlled and uncontrolled epilepsy patients.• The data implicate complement dysregulation and inflammation in the pathogenesis of epilepsy.

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Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy

Cited by 66 publications

References 42 publications

Novel mechanisms and functions of complement

Novel mechanisms and functions of complement

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Complement system biomarkers in epilepsy

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