O1-06-07: Immunotherapy with antibodies to N-terminal amyloid-β peptides reduces cerebral amyloid angiopathy in PDAPP mice

Abstract

Passive immunotherapy with amyloid–β (Aβ) antibodies reduces a number of AD pathologies including parenchymal Aβ plaques, neuritic dystrophy, synaptic loss, and memory function in mouse models, and many of these effects are beginning to be seen in AD patients. In addition to parenchymal deposition of amyloid, AD is also characterized by amyloid fibrils in the cerebral vasculature in the majority of patients, a condition called cerebral amyloid angiopathy (CAA). Previous studies have suggested that immunotherapy does not clear and may increase CAA and the incidence of microhemorrhage. In the present study we demonstrate that certain immunotherapies are surprisingly highly efficacious in removing CAA and that the incidence of microhemorrhage can be modulated by dosage. We examined the effects of passive immunization on CAA in 2 PDAPP mouse studies: one a comparison of antibodies to different Aβ epitopes (3D6, Aβ1–5; 12A11 and 10D5, Aβ3–7; 266 Aβ16–23) at one dose, and a 3D6 dose–response study at 3 doses. CAA clearance and microhemorrhage incidence were assessed after 6 months using Aβ IHC and hemosiderin detection. We found that 3D6 at the highest dose completely cleared CAA, with nearly 100% clearance observed in both studies. In addition, partial clearance was evident at both lower doses as well as with 10D5 and 12A11 treatments. 266 showed no effect on CAA or plaque clearance. Sites of hemosiderin staining were limited to focal, perivascular regions and were almost entirely restricted to meningeal vasculature and sagittal sinus vessels. Lower dose 3D6 groups had significantly reduced hemosiderin ratings compared to the highest dose group, and the 266 and 10D5 groups did not significantly differ from the control. Hemosiderin staining co–localized with Aβ at sites of ongoing clearance in the lower dose 3D6, 12A11, and 10D5 groups. Collectively, these observations showed that removal of CAA at lower doses of 3D6 minimized microhemorrhage over the 6–month study period. These observations suggest that passive immunization can reduce CAA, and modulating antibody dose and duration can significantly mitigate the incidence of microhemorrhage. Immunotherapy can then potentially remove or reverse the CAA that is thought to lead to dysfunction of the microvasculature in AD.