Amyloid-beta vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid - PubMed (original) (raw)

Amyloid-beta vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid

D M Wilcock et al. Neuroscience. 2007.

Abstract

Vaccination with Abeta(1-42) and treatment with NCX-2216, a novel nitric oxide releasing flurbiprofen derivative, have each been shown separately to reduce amyloid deposition in transgenic mice and have been suggested as potential therapies for Alzheimer's disease. In the current study we treated doubly transgenic amyloid precursor protein and presenilin-1 (APP+PS1) mice with Abeta(1-42) vaccination, NCX-2216 or both drugs simultaneously for 9 months. We found that all treatments reduced amyloid deposition, both compact and diffuse, to the same extent while only vaccinated animals, with or without nonsteroidal anti-inflammatory drug (NSAID) treatment, showed increased microglial activation associated with the remaining amyloid deposits. We also found that active Abeta vaccination resulted in significantly increased cerebral amyloid angiopathy and associated microhemorrhages, while NCX-2216 did not, in spite of similar reductions in parenchymal amyloid. Co-administration of NCX-2216 did not attenuate this effect of the vaccine. This is the first report showing that active immunization can result in increased vascular amyloid and microhemorrhage, as has been observed with passive immunization. Co-administration of an NSAID agent with Abeta vaccination does not substantially modify the effects of Abeta immunotherapy. The difference between these treatments with respect to vascular amyloid development may reflect the clearance-promoting actions of the vaccine as opposed to the production-modifying effects proposed for flurbiprofen.

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Figures

Figure 1

Figure 1

Aβ1–42 vaccination, with or without NCX-2216 treatment, produces detectable anti-Aβ antibody titers. The graph shows antibody titers for mice receiving either no treatment (Cont), Aβ1–42 vaccination (vacc), NCX-2216 diet (NCX) or both Aβ1–42 vaccination with NCX-2216 diet (vacc+NCX). Titers are shown as μg IgG per ml serum after dissociation from circulating Aβ. ** indicates P<0.01.

Figure 2

Figure 2

Aβ immunohistochemistry is reduced in all three treatment groups. Aβ immunohistochemistry is shown in the hippocampus for APP+PS1 transgenic mice receiving no treatment (Panel A), Aβ1–42 vaccination (Panel B), NCX-2216 diet (Panel C) or both Aβ1–42 vaccination with NCX-2216 diet (Panel D). In Panel A, CA1: cornu ammonis 1, CA3: cornu ammonis 3, DG: dentate gyrus. Scale bar in Panel A = 120μm.

Figure 3

Figure 3

Quantification of Aβ immunohistochemistry reveals reductions in all three treatment groups compared with control treated APP+PS1 transgenic mice. The graphs show percent area occupied with positive stain for mice receiving either no treatment (cont), Aβ1–42 vaccination (vacc), NCX-2216 diet (NCX) or both Aβ1–42 vaccination with NCX-2216 diet (vacc+NCX). Panel A shows quantification in the frontal cortex while panel B shows quantification in the hippocampus. * indicates P<0.05, ** indicates P<0.01 compared to untreated mice.

Figure 4

Figure 4

Congo red staining is reduced in all three treatment groups. Congo red staining is shown in the hippocampus for APP+PS1 transgenic mice receiving no treatment (Panel A), Aβ1–42 vaccination (Panel B), NCX-2216 diet (Panel C) or both Aβ1–42 vaccination with NCX-2216 diet (Panel D). In Panel A CA1: cornu ammonis 1, CA3: cornu ammonis 3, DG: dentate gyrus. Scale bar in Panel A = 120μm.

Figure 5

Figure 5

Quantification of Congo red staining reveals reductions in total Congo red in all three treatment groups, but increased vascular Congo red following Aβ1–42 vaccination. The graphs show percent area occupied with positive stain for mice receiving either no treatment (cont), Aβ1–42 vaccination (vacc), NCX-2216 diet (NCX) or both Aβ1–42 vaccination with NCX-2216 diet (vacc+NCX). Solid bars indicate values for the frontal cortex while open bars indicate values for the hippocampus. Panel A shows quantification of total Congo red, panel B shows quantification of vascular Congo red and panel C shows calculation of parenchymal Congo red. ** indicates P<0.01 compared to control and as shown in panel B.

Figure 6

Figure 6

CAA- associated microhemorrhage is increased following Aβ1–42 vaccination. Sections are stained for hemosiderin (extravenous iron) with Prussian blue and cells are counterstained with Texas red. Panels A and C show the hippocampus of a control treated APP+PS1 transgenic mouse while panels B and D show the hippocampus of an Aβ1–42 vaccinated APP+PS1 transgenic mouse. For Panels A and B, the scale bar in panel A represents 120μm. Panels C and D are a higher magnification of the area shown in the box of panels A and B, and the scale bar in panel C = 50μm. In Panel A, CA1: cornu ammonis 1, CA3: cornu ammonis 3, DG: dentate gyrus. Panel E shows quantification of Prussian blue staining and is shown as the number of positive profiles per section for mice receiving either no treatment (cont), Aβ1–42 vaccination (vacc), NCX-2216 diet (NCX) or both Aβ1–42 vaccination with NCX-2216 diet (vacc+NCX). ** indicates P<0.01 compared to the control group.

Figure 7

Figure 7

CD45 immunohistochemistry is increased around remaining plaques in mice administered Aβ1–42 vaccination. CD45 immunohistochemistry counterstained with Congo red is shown in the hippocampus for APP+PS1 transgenic mice receiving no treatment (Panel A), Aβ1–42 vaccination (Panel B), NCX-2216 diet (Panel C) or both Aβ1–42 vaccination with NCX-2216 diet (Panel D). In Panel A CA1: cornu ammonis 1, CA3: cornu ammonis 3, DG: dentate gyrus. Scale bar in Panel A = 120μm.

Figure 8

Figure 8

Quantification of CD45 immunohistochemistry reveals increases around remaining deposits following Aβ1–42 vaccination. The graphs show percent area occupied with positive stain for mice receiving either no treatment (cont), Aβ1–42 vaccination (vacc), NCX-2216 diet (NCX) or both Aβ1–42 vaccination with NCX-2216 diet (vacc+NCX). Panels A and B show quantification of total percent area occupied with positive stain for CD45 while panels C and D show calculated ratios of CD45 staining to Congo red. Panels A and C show quantification in the frontal cortex while panels B and D show quantification in the hippocampus. * indicates P<0.05 compared to control APP+PS1 mice.

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