Immunotherapy Reduces Vascular Amyloid-  in PDAPP Mice

Abstract

In addition to parenchymal amyloid-␤ (A␤) plaques, Alzheimer's disease (AD) is characterized by A␤ in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular A␤ (VA␤) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-A␤ antibodies may clear parenchymal amyloid but increase VA␤ and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VA␤ and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VA␤ and microhemorrhage in PDAPP mice by comparing antibodies with different A␤ epitopes (3D6, A␤ 1-5 ; 266, A␤ 16 -23 ) and performing a 3D6 dose-response study. VA␤ and microhemorrhage were assessed using concomitant A␤ immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VA␤ in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VA␤ was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with A␤ deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VA␤ levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VA␤. These observations raise the possibility that A␤ immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.

Aβ Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice

“…In the hippocampus, the area fraction covered with ThioS ϩ ␤-amyloid plaques in antibody-treated APP/PS1 mice was Ͼ60% lower, from 1.32 Ϯ 0.29% in vehicle-treated APP/PS1 animals to 0.48 Ϯ 0.21% ( p ϭ 0.05) in ␣-A␤-treated mice. Progressive accumulation of ␤-amyloid in the vicinity of blood vessels can result in microhemorrhages, and some studies have linked immunotherapy to an initial increase in CAA and microhemorrhages (Pfeifer et decrease during longer treatment periods (Schroeter et al, 2008). To exclude that the ␣-A␤ antibody treatment used here decreased parenchymal A␤ plaques but increased vascular A␤ deposits, we quantified CAA visualized by ThioS staining.…”

Magnetic Resonance Imaging Detection and Time Course of Cerebral Microhemorrhages during Passive Immunotherapy in Living Amyloid Precursor Protein Transgenic Mice

“…Experimental studies of both active and passive A␤ immunization in transgenic mice have confirmed that removal of existing A␤ plaques can occur, sometimes within a matter of days, and this is associated with cognitive benefits (Schenk et al, 1999;Janus et al, 2000;Morgan et al, 2000;Schenk, 2002;Wilcock et al, 2004;Boche et al, 2008). However, several studies have demonstrated an increased incidence of cerebral microhemorrhages ex vivo in aged transgenic mice after a period of immunotherapy (Pfeifer et al, 2002;Racke et al, 2005;Wilcock et al, 2007;Schroeter et al, 2008;Thakker et al, 2009). The discontinued phase II active im-munization trial with aggregated A␤ as an immunogen (AN1792) observed more severe CAA in immunized patients than those without at a similar stage of AD, with multiple cortical hemorrhages in one case (Boche et al, 2008;Thakker et al, 2009).…”

“…Although detection of small (20 -400 M), individual microhemorrhages postmortem in mouse brain is possible by histological examination using Prussian blue (Pfeifer et al, 2002;Racke et al, 2005;Wilcock et al, 2007), it is very time consuming (Pfeifer et al, 2002;Wilcock et al, 2004;Racke et al, 2005;Schroeter et al, 2008). Two further fundamental questions cannot be easily addressed by using the ex vivo approach: 1) When do the microhemorrhages occur during immunotherapy?…”

Advances in the therapy of Alzheimer’s disease: targeting amyloid beta and tau and perspectives for the future

“…Preclinical studies in transgenic mice that generate a surplus of Ab demonstrated that antibodies directed against Ab N-terminus are able to enter the brain and decrease amyloid deposits in brain tissue and cerebral vasculature [61,62]. Moreover, such antibodies inhibit the synaptotoxic actions of Ab oligomers and enhance cognitive skill in APP transgenic mice [63,64].…”