C5aR agonist enhances phagocytosis of fibrillar and non-fibrillar Aβ amyloid and preserves memory in a mouse model of familial Alzheimer’s disease

Abstract

According to the amyloid hypothesis of Alzheimer’s disease (AD) the deposition of prefibrillar and fibrillar Aβ peptide sets off the pathogenic cascades of neuroinflammation and neurodegeneration that lead to synaptic and neuronal loss resulting in cognitive decline. Various approaches to reduce amyloid load by reducing production of the Aβ peptide or enhancing amyloid clearance by primary or secondary immunization have not proven successful in clinical trials. Interfering with the normal function of secretases and suboptimal timing of Aβ peptide removal have been put forward as possible explanations. Complement, an innate component of the immune system, has been found to modulate disease pathology and in particular neuronal loss in the AD mouse model but its mechanism of action is complex. C1Q has been shown to facilitate phagocytosis of Aβ peptide but its Ablation attenuates neuroinflammation. Experiments in AD mouse models show that inhibition of complement component C5a reduces amyloid deposition and alleviates neuroinflammation. Phagocytes including microglia, monocytes and neutrophils carry C5a receptors. Here, a widely used mouse model of AD, 5XFAD, was intermittently treated with the oral C5a receptor agonist EP67 and several neuronal and neuroinflammatory markers as well as memory function were assessed. EP67 treatment enhanced phagocytosis, resulting in a significant reduction of both fibrillar and non-fibrillar Aβ, reduced astrocytosis and preserved synaptic and neuronal markers as well as memory function. Timely and phasic recruitment of the innate immune system offers a new therapeutic avenue of treating pre-symptomatic Alzheimer disease.

Idebenone Regulates Aβ and LPS-Induced Neurogliosis and Cognitive Function Through Inhibition of NLRP3 Inflammasome/IL-1β Axis Activation

“…Second, 3-month-old 5xFAD mice are a model of the early phase of AD and have not yet developed impairments of long-term cognitive ability. Spatial working memory impairment is observed in 3-month-old 5xFAD mice (72,73), but long-term spatial memory deficits are observed only in the intermediate/late phase of AD in this model, i.e., 5xFAD mice older than 6 months (74,75). Thus, future work will investigate whether idebenone improves longterm memory in 6-month-old 5xFAD mice via the Morris water maze test.…”

C5aR1 Mediates the Progression of Inflammatory Responses in the Brain of Rats in the Early Stage after Ischemia and Reperfusion

“…28,29 C5aR1 is widely expressed on various cells in the central nervous system and involved in many pathophysiological processes, including infection, 27 intracerebral hemorrhage, 30,31 spinal cord injury, 32 hypoxic ischemic disease, 33 and neurodegeneration. 34,35 In recent years, several therapeutics for inflammations targeting C5 conversion, C5a, or its receptor C5aR1 were developed gradually. To specifically target the harmful anaphylatoxininduced effects by the use of C5a or C5aR1 antagonists, therefore, was taken for the most promising strategy and presented opportunities for a phase 2 clinical trial in treating bacterial meningitis.…”

“…When the complement system is activated, split fragments C5a and C3a augment the release of inflammatory factors and facilitate the recruitment of monocytes and neutrophils to the inflamed tissues . C5a, which is known as an anaphylatoxin, exerts a detrimental effect inducing tissue injury via its specific receptor C5aR1. , C5aR1 is widely expressed on various cells in the central nervous system and involved in many pathophysiological processes, including infection, intracerebral hemorrhage, , spinal cord injury, hypoxic ischemic disease, and neurodegeneration. , In recent years, several therapeutics for inflammations targeting C5 conversion, C5a, or its receptor C5aR1 were developed gradually. To specifically target the harmful anaphylatoxin-induced effects by the use of C5a or C5aR1 antagonists, therefore, was taken for the most promising strategy and presented opportunities for a phase 2 clinical trial in treating bacterial meningitis .…”

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

“…Importantly, C5a will start the further downstream sequelae, including reactive oxygen species generation as well as platelet activation and a number of other inflammatory mediators ( Barratt-Due et al, 2017 ). This a major reason for blocking the upstream mediators, including C5a in particular, instead of one of all the hundreds of downstream inflammatory mediators generated as a result of C5a responses ( Ward, 2004 ; Panayiotou et al, 2019 ; Li et al, 2020 ). In addition, it is possible that in the CNS, as in the periphery, C5a via C5aR1 signaling synergizes with TLR/NF κ B and the NLRP3 inflammasome activity to trigger potent detrimental inflammatory responses ( Yang et al, 2020 ).…”

“…Importantly, C5a will induce further downstream inflammation, including reactive oxygen species production, and release of the whole network of cytokines from monocytes and macrophages, platelet activation, and a number of other inflammatory mediators ( Barratt-Due et al, 2012 ). This a major reason for blocking mediators like C5a in particular instead of one of all the hundreds of downstream inflammatory mediators generated as a result of C5a responses ( Ward, 2004 ; Panayiotou et al, 2019 ; Li et al, 2020 ).…”