Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3

Pérez-Alcázar, Marta; Daborg, Jonny; Stokowska, Anna; Wasling, Pontus; Björefeldt, Andreas; Kalm, Marie; Zetterberg, Henrik; Carlström, Karl E.; Blomgren, Klas; Ekdahl, Christine T.; Hanse, Eric; Pekna, Marcela

doi:10.1016/j.expneurol.2013.12.013

Cited by 61 publications

(53 citation statements)

References 44 publications

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“…Indeed, mutations in glycolysis and autophagy regulating genes have been connected with both neurodegenerative disease and schizophrenia (Nixon, 2013). Interestingly, C3-deficient mice have reduced learning ability (Perez-Alcazar et al, 2014), and polymorphisms in CD46 and SPAK, an intracellular CD46-interacting protein, were identified as risk factors for schizophrenia and autism in humans (Chehoud et al, 2013; Ramoz et al, 2008). It may thus be worthy assessing a potential connection between complement-regulated metabolic and basic cell physiology pathways in normal and aberrant learning and behavior (Figure 5).…”

Section: New Aspects Of Complement In Human Diseasementioning

confidence: 99%

Complement-Mediated Regulation of Metabolism and Basic Cellular Processes

2016

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Complement is well appreciated as critical arm of innate immunity. It is required for the removal of invading pathogens and functions by direct pathogen destruction and through the activation of innate and adaptive immune cells. However, complement activation and function is not confined to the extracellular space but also occurs within cells. Recent work indicates that complement activation regulates key metabolic pathways and thus can impact fundamental processes of the cell, such as survival, proliferation, and autophagy. Novel identified functions of complement include a key role in shaping metabolic reprogramming, which underlies T cell effector differentiation, and a role as a nexus for interactions with other effector systems, in particular the inflammasome and Notch transcription factor networks. This review focuses on the contributions of complement to basic processes of the cell, in particular the integration of complement with cellular metabolism, and the potential implications in infection and other disease settings.

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Section: New Aspects Of Complement In Human Diseasementioning

confidence: 99%

Complement-Mediated Regulation of Metabolism and Basic Cellular Processes

2016

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“…Complement has also non-immune functions, not least in the central nervous system (CNS), such as synapse elimination [9][10][11][12], and regulation of adult neurogenesis [13] and synaptic function [14]. C3a is a peptide generated by proteolytic activation of complement factor C3.…”

Section: Introductionmentioning

confidence: 99%

Complement Peptide C3a Promotes Astrocyte Survival in Response to Ischemic Stress

et al. 2015

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Astrocytes are the most numerous cells in the central nervous system with a range of homeostatic and regulatory functions. Under normal conditions as well as after ischemia, astrocytes promote neuronal survival. We have previously reported that the complement-derived peptide C3a stimulates neuronal differentiation of neural progenitor cells and protects the immature brain tissue against hypoxic-ischemic injury. Here, we studied the effects of C3a on the response of mouse cortical astrocytes to ischemia. We have found that chemical ischemia, induced by combined inhibition of oxidative phosphorylation and glycolysis, upregulates the expression of C3a receptor in cultured primary astrocytes. C3a treatment protected wild-type but not C3a receptor-deficient astrocytes from cell death induced by chemical ischemia or oxygen-glucose deprivation by reducing ERK signaling and caspase-3 activation. C3a attenuated ischemia-induced upregulation of glial fibrillary acidic protein; however, the protective effects of C3a were not dependent on the presence of the astrocyte intermediate filament system. Pre-treatment of astrocytes with C3a during recovery abrogated the ischemia-induced neuroprotective phenotype of astrocytes. Jointly, these results provide the first evidence that the complement peptide C3a modulates the response of astrocytes to ischemia and increases their ability to cope with ischemic stress.

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“…In support of the first possibility are, as abovementioned, recent findings reporting multiple emerging novel noninflammatory roles of complement in every stage of brain development (Coulthard et al, 2018b), as well as data from genetic studies showing an association between risk variants in complement genes and neurodevelopmental disorders (Warren et al, 1991;Odell et al, 2005;Sekar et al, 2016). In addition, there are studies suggesting that the neuropathological and behavioral phenotypes in genetically modified mouse models with aberrant complement expression in the brain parallel known features of these human developmental brain disorders (Chu et al, 2010;Perez-Alcazar et al, 2014;Sekar et al, 2016;Comer et al, 2019).…”

Section: Introductionmentioning

confidence: 74%

Complement System in Brain Architecture and Neurodevelopmental Disorders

et al. 2020

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Current evidence indicates that certain immune molecules such as components of the complement system are directly involved in neurobiological processes related to brain development, including neurogenesis, neuronal migration, synaptic remodeling, and response to prenatal or early postnatal brain insults. Consequently, complement system dysfunction has been increasingly implicated in disorders of neurodevelopmental origin, such as schizophrenia, autism spectrum disorder (ASD) and Rett syndrome. However, the mechanistic evidence for a causal relationship between impaired complement regulation and these disorders varies depending on the disease involved. Also, it is still unclear to what extent altered complement expression plays a role in these disorders through inflammation-independent or-dependent mechanisms. Furthermore, pathogenic mutations in specific complement components have been implicated in the etiology of 3MC syndrome, a rare autosomal recessive developmental disorder. The aims of this review are to discuss the current knowledge on the roles of the complement system in sculpting brain architecture and function during normal development as well as after specific inflammatory insults, such as maternal immune activation (MIA) during pregnancy, and to evaluate the existing evidence associating aberrant complement with developmental brain disorders.

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Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3

Cited by 61 publications

References 44 publications

Complement-Mediated Regulation of Metabolism and Basic Cellular Processes

Complement-Mediated Regulation of Metabolism and Basic Cellular Processes

Complement Peptide C3a Promotes Astrocyte Survival in Response to Ischemic Stress

Complement System in Brain Architecture and Neurodevelopmental Disorders

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