Antibody-Mediated Clearance of Amyloid-β Peptide from Cerebral Amyloid Angiopathy Revealed by QuantitativeIn VivoImaging

Abstract

Cerebral amyloid angiopathy (CAA) is the accumulation of amyloid-␤ peptide (A␤) in the vessel wall of arteries in the brain. Because CAA is commonly associated with Alzheimer's disease (AD), characterized by parenchymal deposition of the same peptide in the form of senile plaques, there is considerable interest in the relationship of the two deposits in generating human disease. The study of CAA is of particular importance for immunotherapeutic approaches to AD, because reports of anti-A␤ immunotherapy in mice and humans have suggested that, whereas CAA appeared resistant to clearance, its response to this treatment promoted potential adverse effects, including meningoencephalitis. We used multiphoton microscopy and longitudinal imaging to monitor CAA in a mouse model of amyloid deposition to evaluate the effects of anti-A␤ passive immunotherapy. We found detectable clearance of CAA deposits within 1 week after a single administration of antibody directly to the brain, an effect that was short-lived. Chronic administration of antibody over 2 weeks led to more robust clearance without evidence of hemorrhage or other destructive changes. We found that the progressive clearance of A␤ from vessels follows distinct kinetics from what has been previously reported for clearance of plaques (parenchymal deposits of A␤). This quantitative in vivo imaging approach directly demonstrates that CAA in a transgenic mouse model can be cleared with an optimized immunotherapy.

Immunotherapy Reduces Vascular Amyloid- in PDAPP Mice

“…Our results are in keeping with recently published studies involving the direct application of an N-terminal antibody to the brain in which VA␤ was cleared without evidence of microhemorrhage (Prada et al, 2007). The clearance seen in our studies was accompanied by an increased incidence of microhemorrhage that could be controlled by lowering the antibody dosage.…”

“…Currently A␤-targeted therapeutic approaches for AD have not been shown to reduce vascular amyloid deposition in chronic in vivo preclinical paradigms. However, there is evidence that the direct application of amyloid antibodies to the brain (Prada et al, 2007) and blocking the apolipoprotein E/A␤ interaction (Sadowski et al, 2006) reduce VA␤.…”

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

“…Preliminary data from the phase I and II AN-1972 clinical trials suggest that immunotherapy may be effective early in AD, well before amyloid is extensively deposited and an advanced degree of vasculature is compromised (19,51). Recent preclinical studies provide evidence that a reduction of both parenchymal plaques and CAA is achieved upon icv injection of an adeno-associated viral vector that expresses anti-A␤ single-chain variable fragments in neonatal transgenic CRND8 mice (52), or by local application of antibodies onto the cortex of Tg2576 mice at 10 to 13 months of age, when CAA follows a linear mode of progression (53). Our experiments in aged Tg2576 mice, with near-saturating levels of CAA and an abundant plaque pathology (41)(42)(43)(44), augment these findings and demonstrate that icv-targeted delivery of anti-A␤ antibodies not only reduces the behavioral deficit, parenchymal plaques, and associated pathology (eg, astrogliosis, dystrophic neurites), but also provides a previously unexpected opportunity to mitigate CAA and associated micro-hemorrhages despite the advanced disease stage.…”

Strategies for the Inhibition of Protein Aggregation in Human Diseases

“…[219] Examples of active immunization undertaken to enhance the progressive clearance of Ab [220] include the humanized monoclonal antibody MABT5102A, also known as anti-Ab, which is undergoing phase I clinical trials, [221] and ACC-001, an active Ab immunotherapeutic conjugate that has completed phase I trials and is about to enter phase II trials. With regard to passive immunotherapy, [222] bapineuzumab is starting phase III clinical trials. Active immunization has also been developed against a-syn aggregates [223,224] and against PrP Sc .…”