Complement protein C5a enhances the β-amyloid-induced neuro-inflammatory response in microglia in Alzheimer’s disease

Abstract

Objective: The dysregulation of neuro-inflammation is one of the attributes of the pathogenesis of Alzheimer’s disease (AD). Over-expression of complement proteins co-localizes with neurofibrillary tangles, thereby indicating that a complement system may be involved in neuro-inflammation. Here, we report the influence of complement activation on the neuro-inflammation using a microglial cell line. Methods: first, we performed a cytotoxic assay using the microglial cells BV-2. Second, after treatment of BV-2 cells with Aβ42 and/ or C5a, the anaphylatoxin derived from C5, we determined the expression levels of the pro-inflammatory factors TNF-α, IL-1β, and IL-6. Finally, we explored whether this neuroinflammatory response was mediated by JAK/ STAT3 signaling. Results: C5a had an enhanced effect on the neural cell viability of BV-2 cells treated with Aβ42. In addition, C5a also increased the Aβ-induced neuro-inflammatory response, and these effects were blocked by the C5aR antagonist, PMX205. Finally, we demonstrated that the neuro-inflammatory responses induced by Aβ and C5a were mediated through JAK/STAT3 signaling. By blocking this pathway with an antagonist, AG490, the expression of TNF-α, IL-1β, and IL-6 was alleviated. Conclusion: The complement protein C5a could exaggerate the Aβ-induced neuroinflammatory response in microglia, and C5aR may be a potential therapeutic tool for AD treatment.

Complement: Bridging the innate and adaptive immune systems in sterile inflammation

“…In both development and disease, complement opsonins (i.e., C1q and C3b) facilitate microglia‐mediated synaptic pruning and phagocytosis of cellular debris 148‐151 and C1q can affect microglial cytokine production in a similar manner to that in DCs whereby apoptotic blebs modulate the response, although whether or not microglia interact with T cells in this manner is not known 152,153 . Likewise, anaphylatoxins (i.e., C3a and C5a) have a number of canonical effects on glial cells including driving chemotaxis, 154,155 promoting cytokine production, 156,157 and activating the inflammasome, 158,159 but may also have a number of direct effects on neurons including limiting excitotoxity, 160 promoting neurogenesis, 161 and driving neuronal stem cell proliferation in brain cancer 162 . Such diverse capabilities are also exhibited by MAC, which has canonical cytolytic effects that are driven in autoimmune conditions by autoantibody activation of the classical pathway 163‐166 and immunomodulatory and protective effects on glia 167,168 .…”

Brain–Immune Interactions and Neuroinflammation After Traumatic Brain Injury

“…In fact, accumulation of these complement proteins generates damaged neurons, increases numbers of activated glial cells (Bradt et al, 1998), and, through neuronal C3a/C3aR signaling, disrupts dendritic morphology and network function (Lian et al, 2015). The Aβ-induced neuroinflammation response is also exaggerated by C5a/C5aR signaling (An et al, 2018), demonstrating another link between Aβ and complement activation. Similarly, the role of the complement pathway has been investigated in the context of the neuroinflammatory autoimmune neurodegenerative disease MS.…”

Synaptic Pruning in Alzheimer’s Disease: Role of the Complement System

“…The authors determined the expression levels of the pro-inflammatory factor’s TNF-α, IL-1β, and IL-6 and explored whether the neuroinflammatory response, caused by Aβ 42 treatment of BV-2 cells, was mediated by JAK/STAT3 signaling [ 54 ].…”