Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-β plaque load in the TgCRND8 mouse model of Alzheimer's disease

Abstract

Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Aβ), which circulate in the bloodstream and remove Ab from the brain [1,2]. In mouse models of AD, the administration of anti-Aβ antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Ab plaque pathology [3,4]. Therefore, delivering anti-Aβ antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS) is known to transiently-enhance the permeability of the blood-brain barrier (BBB) [5], allowing intravenously administered therapeutics to enter the brain [6-8]. Our goal was to establish that anti-Aβ antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) [9] can reduce plaque pathology. To test this, TgCRND8 mice [10] received intravenous injections of MRI and FUS contrast agents, as well as anti-Aβ antibody, BAM- 10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Ab plaques in targeted cortical areas. Four days post-treatment, Ab pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Aβ antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology. Copyright: © 2010 Jordão et al.