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Background Clinical studies of β-amyloid (Aβ) immunotherapy in Alzheimer's disease (AD) patients have demonstrated reduction of central Aβ plaque by positron emission tomography (PET) imaging and the appearance of amyloid-related imaging abnormalities (ARIA). To better understand the relationship between ARIA and the pathophysiology of AD, we undertook a series of studies in PDAPP mice evaluating vascular alterations in the context of central Aβ pathology and after anti-Aβ immunotherapy. Methods We analyzed PDAPP mice treated with either 3 mg/kg/week of 3D6, the murine form of bapineuzumab, or isotype control antibodies for periods ranging from 1 to 36 weeks and evaluated the vascular alterations in the context of Aβ pathology and after anti-Aβ immunotherapy. The number of mice in each treatment group ranged from 26 to 39 and a total of 345 animals were analyzed. Results The central vasculature displayed morphological abnormalities associated with vascular Aβ deposits. Treatment with 3D6 antibody induced clearance of vascular Aβ that was spatially and temporally associated with a transient increase in microhemorrhage and in capillary Aβ deposition. Microhemorrhage resolved over a time period that was associated with a recovery of vascular morphology and a decrease in capillary Aβ accumulation. Conclusions These data suggest that vascular leakage events, such as microhemorrhage, may be related to the removal of vascular Aβ. With continued treatment, this initial susceptibility period is followed by restoration of vascular morphology and reduced vulnerability to further vascular leakage events. The data collectively suggested a vascular amyloid clearance model of ARIA, which accounts for the currently known risk factors for the incidence of ARIA in clinical studies.

Background: Cerebral amyloid angiopathy is a common neuropathological feature of Alzheimer’s disease and is characterized by vascular deposition of fibrillar amyloid -protein (VA ). Vascular structural changes are associated with VA deposits, including localized loss of smooth muscle cells (SMC) and changes in extracellular matrix (ECM). Passive immunization with antibodies to the A N-terminus (3D6, aa 1-5) has been shown to effectively reduce amyloid deposition in the vasculature of PDAPP transgenic mice. In the present study we characterized structural changes induced by amyloid on SMC and ECM of PDAPP mouse vessels and assessed the effects of passive immunotherapy. Methods: Mice were immunized weekly for either 3 or 9 months with 1 or 3 mg/Kg of 3D6 antibody. High-resolution, quantitative IHC analyses of vascular components ( -actin for SMC and collagen-IV for ECM) were performed on meningeal vessels from the sagittal sinus, where VA deposition is prominent ( 70% of vessels affected). Microhemorrhage events were monitored by hemosiderin detection or ferritin immunohistochemistry. Results: We found that changes in the vascular wall are invariably associated with VA , and they included both degeneration (decreased thickness) and hyperplasia/hypertrophy (increased thickness) of SMC and ECM. These two contrasting findings were often observed in the same vessel and were not present in wild type animals or PDAPP vessels lacking amyloid. The extreme degrees of thickening and thinning of the SM resulted in a widely variable vascular phenotype in untreated PDAPP mice. Passive immunotherapy restored the pattern of vascular SMC and ECM thicknesses and reduced the phenotypic variability in a doseand time-dependent manner, with the high dose of 3D6 reaching control levels (wild type) at 9 months. Although the incidence of microhemorrhage increased in the 3-month group, it reduced to control levels after 9 months of treatment. Conclusions: Our results suggest that passive immunotherapy allows the recovery of meningeal vessels from amyloid-induced structural changes. Furthermore, the treatment-related increase in microhemorrhage appears to be a transient event that resolves during VA clearance. Mechanisms of repair may be triggered by VA removal, which ultimately lead to recovery from vascular dysfunction. Experiments to assess this possibility are in progress.

Passive immunotherapy with amyloid(A ) antibodies reduces a number of AD pathologies including parenchymal A 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 A epitopes (3D6, A 1-5; 12A11 and 10D5, A 3-7; 266 A 16-23) at one dose, and a 3D6 dose-response study at 3 doses. CAA clearance and microhemorrhage incidence were assessed after 6 months using A IHC and hemosiderin detection.