IC-02-02: MRI detection and time course of cerebral microhemorrhages during Aβ antibody treatment in living APP transgenic mice

Abstract

In recent years immunotherapy-based approaches to treat Alzheimer's disease have become the subject of intensive research. However, an important mechanistic-related safety concern is the risk of exacerbating incidence of microhemorrhage that may be associated with fast removal of β-amyloid (Aβ) deposits found in blood vessels or brain parenchyma. Several preclinical reports with non-selective antibodies that bind and remove deposited Aβ plaque and soluble Aβ have indicated an increased incidence of microhemorrhages in aged APP transgenic mice using histological techniques. While this is less likely to occur with antibodies highly selective for soluble Aβ, a rapid detection of microhemorrhages in APP transgenic mice has not been described and histological analysis can take several months before this risk is assessed. The aim of this study was to develop an in vivo cerebral microhemorrhage biomarker using MRI and determine the effects of 12 weeks treatment with two anti Aβantibodies, 6G1 and 8F5, compared to PBS control in aged Tg2576 mice. MRI imaging was performed on a 7.0T/21cm horizontal bore scanner using gradient echo T2*-weighted MR microscopy (100 μM × 100 μM × 400 μM). Cerebral microhemorrages using MRI were quantified at baseline and after 12 weeks of treatment and compared to histological hemosiderin staining in each animal. Two anti Aβantibodies were tested: 6G1 is a non-selective antibody that binds soluble and deposited Aβ, whereas 8F5 is a more selective antibody with a lower affinity for deposited Aβ. Our results show that MRI can reliably detect microhemorrhages of ≥60 μM size at baseline and after 12 weeks of treatment in the same animals, and significantly correlates with histological readings. 6G1 and 8F5, however, both increased microhemorrhage incidence when compared to PBS treated Tg2576 mice. A new imaging safety biomarker was developed and can be readily applied to preclinical antibody screening in a longitudinal manner.A highly selective antibody for soluble Aβ is needed to address the question of whether antibodies that do not bind to deposited Aβ have no microhemorrhage liability.