Antibodies Targeted to the Brain with Image-Guided Focused Ultrasound Reduces Amyloid-β Plaque Load in the TgCRND8 Mouse Model of Alzheimer's Disease

Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (A beta), which circulate in the bloodstream and remove A beta from the brain [1,2]. In mouse models of AD, the administration of anti-A beta antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing A beta plaque pathology [3,4]. Therefore, delivering anti-A beta 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-A beta 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-A beta 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 A beta plaques in targeted cortical areas. Four days post-treatment, A beta pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-A beta antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology.