The impact of Neutrophil Inhibition on ARIA Incidence Following 3D6 Administration in Mice

 

Background: Administration of anti-amyloid antibodies to treat Alzheimer’s disease has been shown to produce microhemorrhages in the brains of humans and amyloid mouse models, known as ARIA-H, and while we are becoming more aware of risk factors, an exact mechanism is not known. Some proposed mechanisms include increased amyloid load at the increasingly fragile arteriole interface, microglial recruitment of monocytes and T-cells, or direct microglial attack of the vasculature by interaction with the Fc regions of antibody bound to vascular amyloid.

Neutrophils, the most abundant peripheral immune cell, have previously been shown to contribute to Alzheimer’s disease progression. These cells also respond to the presence of Fc regions on antibodies while being equipped with tools that can cause severe endothelial damage.

Methods: 18-month old Tg2576 mice were administered weekly 3D6 injections with thrice weekly murinized anti-Ly6G antibody to chronically deplete neutrophils over 8 weeks. Depletion efficacy was tracked using Flow Cytometry, in vivo tracking of amyloid deposition and vascular leakage was performed monthly using multiphoton microscopy, and microhemorrhages were assessed after 8 weeks of treatment using Prussian Blue staining.

Results: Chronic depletion of neutrophils did not impact the rate of amyloid deposition or removal, however, vascular leakage was attenuated in mice treated with 3D6 and the rate of microhemorrhages was greatly reduced to near-IgG treated controls.

Conclusions: While still preliminary, these results support the hypothesis that neutrophils are involved in vascular damage from anti-amyloid immunotherapies.