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


Autoři: Elena Panayiotou aff001;  Eleni Fella aff002;  Savanna Andreou aff002;  Revekka Papacharalambous aff001;  Petroula Gerasimou aff003;  Paul Costeas aff003;  Stella Angeli aff002;  Ioanna Kousiappa aff004;  Savvas Papacostas aff002;  Theodoros Kyriakides aff001
Působiště autorů: Neurology Clinic A, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus aff001;  Cyprus School of Molecular Medicine, Nicosia, Cyprus aff002;  Karaiskakio Foundation, Nicosia, Cyprus aff003;  Neurology Clinic B, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225417

Souhrn

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.

Klíčová slova:

Alzheimer's disease – Immunoblotting – Immunohistochemistry techniques – Microglial cells – Mouse models – Neutrophils – Phagocytes – Phagocytosis


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2019 Číslo 12