University of Cambridge > Talks.cam > Departmental Seminar Programme, Department of Veterinary Medicine > Broad complement inhibition in a mouse model of Alzheimer’s disease

Broad complement inhibition in a mouse model of Alzheimer’s disease

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Alzheimer’s Disease (AD), the commonest form of dementia, is a neurodegenerative disorder characterized by the presence of extracellular neuronal plaques, intracellular neurofibrillary tangles, neuroinflammation and neuronal cell loss. Although its aetiology remains largely unknown, recent genome-wide association studies (GWAS) have highlighted the role of the immune system, finding multiple immune related genes, including those encoding members of the complement cascades such as Complement Receptor 1 (CR1), as susceptibility factors. Moreover, complement components have been found in association with plaques and tangles, the histopathological hallmarks of AD, in postmortem AD brain. Thus, a role for complement-mediated neuroinflammation in modulating disease progression has been proposed and CR1 is a potential target for therapeutics development. In order to validate such an approach to disease modification, we performed an in vivo study using two compounds targeting CR1 and thereby inhibiting complement at the level of the convertases C3/C5. Crry-Ig is a rodent functional analogue of human CR1 that has been fused with the Fc portion of IgG (160 KDa) and Mirococept (APT070) is a 23KDa compound containing the 3 amino-terminal (Nt) repeats of human complement receptor 1 (CR1), currently in phase 2a trials for kidney transplantation protection in man. Here we show that the administration of these compounds to 14-15 month old Tg2576, a mouse model of amyloidosis and neuroinflammation but not of tau pathology or neuronal cells loss, resulted in substantial reduction in amyloid pathology and microgliosis while the levels of GFAP reactive astrocytes were not affected. Together, these findings suggest that complement inhibition could be beneficial in slowing the progression of AD-related amyloid pathology and in reducing neuroinflammation mediated by reactive microglia in the AD brain.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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