Immunotherapy reduces vascular amyloid-β in PDAPP mice

In addition to parenchymal amyloid-beta (A beta) plaques, Alzheimer's disease (AD) is characterized by A beta in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular A beta(VA beta) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-A beta antibodies may clear parenchymal amyloid but increase VA beta and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VA beta 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 beta and microhemorrhage in PDAPP mice by comparing antibodies with different A beta epitopes (3D6, A beta(1-5); 266, A beta(16-23)) and performing a 3D6 dose-response study. VA beta and microhemorrhage were assessed using concomitant A beta immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VA beta in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VA beta 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 beta deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VA beta levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VA beta. These observations raise the possibility that A beta immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.