High glucose‐induced complement component 3 up‐regulation via RAGE‐p38MAPK‐NF‐κB signalling in astrocytes: In vivo and in vitro studies

Abstract

Diabetes is considered as a risk for cognitive decline, which is characterized by neurodegenerative alteration and innate immunity activation. Recently, complement 3 (C3), the critical central component of complement system, has been reported to play a key role in neurodegenerative alterations under pathological condition. Receptor for advanced glycation end products (RAGE) activation is confirmed to mediate several inflammatory cytokines production. However, whether C3 activation participates in the diabetic neuropathology and whether this process is regulated by RAGE activation remains unknown. The present study aimed to investigate the role of C3 in streptozotocin‐induced diabetic mice and high glucose‐induced primary astrocytes and the underlying modulatory mechanisms. The decreased synaptophysin density and increased C3 deposition at synapses were observed in the diabetic brain compared to the control brain. Furthermore, the elevated C3 was co‐localized with GFAP‐positive astrocytes in the diabetic brain slice in vivo and high glucose‐induced astrocytes culture in vitro. Diabetes/high glucose‐induced up‐regulation of C3 expression at gene, protein and secretion levels, which were attenuated by pre‐treatment with RAGE, p38MAPK and NF‐κB inhibitors separately. These results demonstrate that high glucose induces C3 up‐regulation via RAGE‐ p38MAPK‐NF‐κB signalling in vivo and in vitro, which might be associated with synaptic protein loss.

Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation

“…Interestingly, C3 levels in our data were increased in GFAP+ astrocytes. Astrocytic C3 production may modulate synaptic density, as observed in models of Alzheimer's disease (Lian et al, 2015(Lian et al, , 2016Luchena et al, 2018), amyotrophic lateral sclerosis (Heurich et al, 2011), perioperative neurocognitive disorder (Xiong et al, 2018) and diabetes (Zhao et al, 2018). We now show that there may be a similar phenomenon in the mIA model of schizophrenia.…”

Gray Matter Abnormalities in Type 1 and Type 2 Diabetes: A Dual Disorder ALE Quantification

“…Chronic hyperglycemia is a potential determinant for diabetes-induced problems in the brain, as it could cause metabolic and molecular alterations, leading to neuron dysfunction or death in the brain (Tomlinson and Gardiner, 2008 ). Similar to Alzheimer's disease (AD), tau phosphorylation and activation of advanced glycation end products (AGE) have been known to contribute to multiple proinflammatory cytokine release that eventually leads to synapse reduction and neuronal loss in diabetic brain (Zhao et al, 2018 ). Consequently, the resulting neuronal loss and gray matter atrophy that accounted for the frequently observed cognitive dysfunctions in DM are observable by brain MRI as GMV reductions (Brands et al, 2005 ).…”

Complement Properdin Regulates the Metabolo-Inflammatory Response to a High Fat Diet

“…In fact, C3 levels associate with body mass indices in obesity [79]. Increased engagement of RAGE (Receptor for advanced glycation end products)/p38MAPK-NF-κB pathway may itself lead to increased production of C3 [80]. However, lipoxidation, the extent to which chronically elevated lipoproteins are oxidatively modified [81], is present and likely confounds identification of the trigger of complement activation [82].…”