Amyloid-beta antibody treatment leads to rapid normalization of plaque-induced neuritic alterations

Abstract

The accumulation of amyloid-beta into insoluble plaques is a characteristic feature of Alzheimer's disease. Neuronal morphology is distorted by plaques: rather than being essentially straight, they are substantially more curved than those in control tissue, their trajectories become altered, and they are frequently distended or swollen, presumably affecting synaptic transmission. Clearance of plaques by administration of antibodies to amyloid-beta is a promising therapeutic approach to the treatment of Alzheimer's disease, leading to stabilization of dementia by an unknown cellular mechanism. The effect of plaque clearance on plaque-induced neuronal alterations has not been studied previously. Here we show that both plaques and neuritic lesions are reversible in a strikingly short period of time after administration of a single dose of amyloid-beta antibody. Amyloid clearance and recovery of normal neuronal geometries were observed as early as 4 d and lasted at least 32 d after a single treatment. These results demonstrate that, once plaques are cleared, neuronal morphology is self-correcting and that passive antibody treatment has the potential to reverse neuronal damage caused by Alzheimer's disease and, hence, directly impact cognitive decline. Moreover, the rapid normalization of neuritic dystrophy suggests an unexpected degree of plasticity in the adult nervous system.

Figure 1.

Application of anti-amyloid antibody 10D5 clears amyloid-β plaques. Amyloid-β plaque clearance occurred only in cortical tissue treated with 10D5. Amyloid protein was immunostained with fluorescent 3D6. a, Untreated area of cortex in animal treated with 10D5. Plaques are clearly visible (arrow). Scale bar, 50 μm. b, Plaques are absent in treated area from the same animal. c, Untreated area of cortex in animal treated with human anti-tau antibody 16B5. d, Treated area of cortex from same animal as in c. e, Comparison of amyloid burden measured with 3D6 antibody under different experimental conditions. The values are the means; error bars indicate SD.

Figure 2.

Amyloid-β clearance restores the morphology of neurites. a, Untreated area of cortex from 10D5-treated animal, immunostained with Cy-3-SMI-32. b, Plaques are clearly visible with 3D6 immunostaining. c, Overlay of a and b showing both plaques and dystrophic neurites. d, Treated area of cortex in same animal as a. Neurites are noticably straighter. e, Plaques are absent in treated 3D6 immunostained area, corrected for autofluorescence. f, Overlay of d and e. Scale bar, 50 μm.

Figure 3.

Comparison of curvature ratios from different experimental conditions. Top, Mean curvature ratio histogram for each experimental condition. Bottom, Comparison of curvature ratios for the different experimental conditions. The values are the medians ± median absolute deviations across animals for each condition.