C5a Increases the Injury to Primary Neurons Elicited by Fibrillar Amyloid Beta

Abstract

C5aR1, the proinflammatory receptor for C5a, is expressed in the central nervous system on microglia, endothelial cells, and neurons. Previous work demonstrated that the C5aR1 antagonist, PMX205, decreased amyloid pathology and suppressed cognitive deficits in two Alzheimer's Disease (AD) mouse models. However, the cellular mechanisms of this protection have not been definitively demonstrated. Here, primary cultured mouse neurons treated with exogenous C5a show reproducible loss of MAP-2 staining in a dose-dependent manner within 24 hr of treatment, indicative of injury to neurons. This injury is prevented by the C5aR1 antagonist PMX53, a close analog of PMX205. Furthermore, primary neurons derived from C5aR1 null mice exhibited no MAP-2 loss after exposure to the highest concentration of C5a tested. Primary mouse neurons treated with both 100 nM C5a and 5 µM fibrillar amyloid beta (fAβ), to model what occurs in the AD brain, showed increased MAP-2 loss relative to either C5a or fAβ alone. Blocking C5aR1 with PMX53 (100 nM) blocked the loss of MAP2 in these primary neurons to the level seen with fAβ alone. Similar experiments with primary neurons derived from C5aR1 null mice showed a loss of MAP-2 due to fAβ treatment. However, the addition of C5a to the cultures did not enhance the loss of MAP-2 and the addition of PMX53 to the cultures did not change the MAP-2 loss in response to fAβ. Thus, at least part of the beneficial effects of C5aR1 antagonist in AD mouse models may be due to protection of neurons from the toxic effects of C5a.

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

“…In the present study, C5a aggravated the cytotoxic effect induced by Aβ 42 in BV-2 cells, consistent with previous findings, in which C5a resulted in less Aβ 42 -induced damage to primary neurons isolated from C5a receptor knockout (C5aR1KO) mice [16]. Moreover, C5a enhanced the neuro-inflammatory response stimulated by Aβ 42 in BV-2 cells.…”

“…Continuously activated complement system results in excessive production of C5a and subsequently exaggerates the neuro-inflammatory response [15]. In addition, C5a enhances the injury of fibrillary amyloid β to the primary neurons [16). Hence, blocking the C5a/C5aR signaling activation axis alleviates the neuro-inflammatory alterations to AD pathologies.…”

Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning

“…The classical pathway of the complement system has been repeatedly implicated in the process of synaptic pruning since the pioneering study of Stevens et al ( 4 ). A detrimental role of the excessive activation of C1q and C3 ( 6 ), and other downstream complement components ( 31 , 32 ) leading to synapse and/or neuronal loss has been identified in neurodegenerative pathology. Despite the significance of complement-mediated synapse elimination in health and disease, knowledge about the molecular changes leading to C1q-tagged synapses is limited.…”

Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System

“…Aβ fibrils activate and consume complement classical and alternative pathways in vitro and generate C3a, C5a, and TCC (119, 126). C5a administration resulted in death of primary mouse neurons in culture; this could be blocked by addition of C5aR1 antagonist PMX53, demonstrating that C5a (acting via C5aR1) is sufficient to induce neuronal cell death in vitro (127). Animal models have underpinned the majority of research into roles and mechanisms of complement in AD.…”