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

Elena Panayiotou,Theodoros Kyriakides,Paul Costeas,Petroula Gerasimou,Ioanna Kousiappa,Revekka Papacharalambous,Savanna Andreou,Savvas Papacostas,Eleni Fella,Stella Angeli,Wataru Araki

doi:10.1371/journal.pone.0225417

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.

Highlights

Alzheimer’s disease (AD) is primarily a progressive neurodegenerative disease of the brain causing either sporadic or familial dementia
At the same time 14 age/sex matched 5XFAD mice and 8 wild type (B6SJLF1/J) animals were kept as controls on plain drinking water
Considering the steep increase in cerebral Aβ in the 5XFAD mice, the remaining 8 animals were treated with EP67 for one week at the end of every month from the end of month three until they reached their 6th month of age, when they received their final treatment tested in the maze and sacrificed

Summary

Introduction

Alzheimer’s disease (AD) is primarily a progressive neurodegenerative disease of the brain causing either sporadic or familial dementia. The presence of these blood-borne phagocytes potentially modulates disease progression by attenuating the accumulation of Aβ plaques [8] Considering these recent data it may be therapeutically prudent to enhance phagocytosis of Aβ by activating local microglia and recruit phagocytes from the periphery in an attempt to interrupt the amyloid cascade. The agonist was originally generated by substituting certain amino acids in C5a and attaching a methyl group to the nitrogen atom on the amide bond between proline and leucine As a result, these structural adjustments restrict and extend the backbone’s conformation creating biased topochemical features that allow for a conformational distinction between C5a-like inflammatory and immune stimulatory activity. C5aR agonist enhances phagocytosis of amyloid enhanced phagocytosis, of both fibrillar and non-fibrillar Aβ, to a level that normalizes behavioural performance and preserves synaptic integrity

Materials and methods

Results

Discussion