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. 2009 Jul 14:1280:178-85.
doi: 10.1016/j.brainres.2009.05.045. Epub 2009 May 22.

A single dose of passive immunotherapy has extended benefits on synapses and neurites in an Alzheimer's disease mouse model

Anete Rozkalne  1 , Tara L Spires-Jones, Edward A Stern, Bradley T Hyman
Affiliations

A single dose of passive immunotherapy has extended benefits on synapses and neurites in an Alzheimer's disease mouse model

Anete Rozkalne et al. Brain Res. .

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory and cognition. One of the major neuropathological hallmarks is the accumulation of the extracellular senile plaques that are mainly composed of amyloid beta (Abeta) protein. Plaques are associated with synapse loss, dystrophic neurites and altered neurite trajectories. A reversal of such morphological changes has been observed days after single dose anti-Abeta immunotherapy. In this study we investigated the extended effects of a single dose of passive anti-Abeta immunotherapy on morphological changes associated with senile plaques. We found that although plaque burden was not reduced 30 days after immunotherapy, there were fewer dystrophic neurites around each plaque, a recovery of synapse density, and normalization of neurite curvature near plaques. Taken together these results suggest that a single dose of immunotherapy is sufficient to cause lasting benefits to the morphology of cortical neurons, implying substantial plasticity of neural circuits despite the continued presence of plaques.

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Figures

Fig 1
Fig 1
Plaque burden 30 days after anti Aβ immunotherapy treatment. Tg2576 and age-matched non-transgenic animals were treated with topical application of either anit-Aβ antibody or anti human tau antibody. The area treated with antibody is outlined in red in panel (A) and is referred to in text as the treated cortex. (B) Plaques were immunolabeled with R1282 primary antibody and visualized with Alexa488. (C) There was no difference in cortical plaque burden between animals treated with an anti Aβ antibody 3D6 and those treated with control antibody 12E8 (p<0.05). Control non-transgenic animals had no plaques as expected. Scale bar 50 μm. Data presented as mean ± SD. Panel with the coronal section was modified from the high resolution mouse brain atlas (http://www.hms.harvard.edu/research/brain/atlas.html).
Fig 2
Fig 2
Effects of passive immunotherapy on axonal dystrophies. (A) Plaque-associated axonal dystrophies (arrows) were analyzed on sections stained with SMI312 (green) and R1282 to label plaques (red). (B) Quantification shows that a single topical treatment with an antibody to Aβ caused a reduction in the average number of dystrophic axonal swellings per plaque 30 days after the treatment (** p<0.001). The effect on axons was observed only in the area treated with anti Aβ antibody and was not seen in the untreated area or in animals treated with irrelevant anti human tau antibody (12E8). Scale bar 20 μm. Data presented as mean ± SD.
Fig 3
Fig 3
Presynaptic terminal density increases 30 days after a single dose of passive immunotherapy treatment. (A) SY38 synaptophysin staining (green) shows presynaptic terminal loss in the area of cortex occupied by R1282 labeled (red) plaques (arrows). (B) A box plot of synaptophysin optical density data shows that there is a trend towards 55% presynaptic terminal loss in animals treated with the control anti tau antibody compared to non-transgenic animals (# Mann-Whitney test p=0.0527). Presynaptic terminal density recovered in tissue treated with anti Aβ antibody (3D6) compared to tissue treated with anti tau antibody (* Mann-Whitney test p<0.01). The recovery occurred despite persistent plaque pathology. Scale bar 50 μm. Optical density data were not normally distributed thus are presented in box plots with median, maxima, and minima shown.
Fig 4
Fig 4
Effects of single dose passive immunotherapy treatment on axon curvature ratios. (A) Axon curvature ratios were measured on SMI312 labeled axons (red) in proximity to Thioflavin S positive plaques (blue). (B) After single dose topical application of antibody to Aβ (3D6) axons close (<50 μm) to plaque were as curved as axons far (>50 μm) from plaque (p>0.05), however without reaching the level of non-transgenic animals. Axons of animals treated with anti tau antibody were significantly more curved close to plaques compared to far from plaques (* p<0.05). Control animals had significantly straighter axons compared to transgenic animals (p<0.05). Scale bar 10 μm. Data presented as mean ± SD.
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