In Vivo Detection of Amyloid Plaques by Gadolinium-Stained MRI Can Be Used to Demonstrate the Efficacy of an Anti-amyloid Immunotherapy.

Mathieu D Santin,Caroline Cohen,Thomas Debeir,Thomas Rooney,Laurent Pradier,Thierry Delzescaux,Marc Dhenain,Michel E Vandenberghe,Anne-Sophie Herard

doi:10.3389/fnagi.2016.00055

Abstract

Extracellular deposition of β amyloid plaques is an early event associated to Alzheimer’s disease. Here, we have used in vivo gadolinium-stained high resolution (29∗29∗117 μm3) magnetic resonance imaging (MRI) to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952) directed against protofibrillar and fibrillary forms of Aβ. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-months-old animals, but not in 5.5-months animals compared to mice treated with a control antibody (DM4). Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-months SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disease of the central nervous system
Three-dimensional MR images of amyloid precursor protein (APP)/presenilin 1 (PS1) and PS1 mice were recorded with a resolution of 29∗29∗117 μm3
Several magnetic resonance imaging (MRI) approaches have been developed to detect individual amyloid plaques, but none of them were used to follow-up a therapy in vivo and in a longitudinal way

Summary

INTRODUCTION

Alzheimer’s disease (AD) is the most common neurodegenerative disease of the central nervous system. SAR255952 is a mouse monoclonal aglycosylated IgG1 antibody engineered to reduce the risk of vasogenic edemas and microhemorrhages that have been associated to anti-amyloid immunotherapies (Pradier et al, 2013) These potential side effects of immunotherapies have been revealed by clinical trials that highlighted signal changes on MR images [ called amyloid imaging related abnormalities (ARIA); Sperling et al, 2011]. SAR255952 is an aglycosyled form of 13C3 The rationale for this aglycosylation is based on the fact that classical antiamyloid monoclonal glycosylated antibodies can induce Fc-γ receptor-mediated overactivation of microglial cells as well as activation of the complement pathway that may contribute to an inappropriate proinflammatory response leading to vasogenic edemas or cerebral microhemorrhages (Lue and Walker, 2002; Adolfsson et al, 2012). MRI, as well as histology, showed a reduction of amyloid load in the SAR255952-treated animals

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION