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

PLoS One. 2010 May 11;5(5):e10549. doi: 10.1371/journal.pone.0010549.

Abstract

Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Abeta), which circulate in the bloodstream and remove Abeta from the brain. In mouse models of AD, the administration of anti-Abeta antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Abeta plaque pathology. Therefore, delivering anti-Abeta 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), allowing intravenously administered therapeutics to enter the brain. Our goal was to establish that anti-Abeta antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) can reduce plaque pathology. To test this, TgCRND8 mice received intravenous injections of MRI and FUS contrast agents, as well as anti-Abeta 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 Abeta plaques in targeted cortical areas. Four days post-treatment, Abeta pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Abeta antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / immunology*
  • Animals
  • Antibodies / administration & dosage
  • Antibodies / therapeutic use*
  • Blood-Brain Barrier / diagnostic imaging
  • Blood-Brain Barrier / pathology
  • Brain / pathology*
  • Disease Models, Animal
  • Echoencephalography
  • Injections, Intravenous
  • Magnetic Resonance Imaging*
  • Mice
  • Mice, Transgenic
  • Permeability
  • Plaque, Amyloid / diagnostic imaging
  • Plaque, Amyloid / pathology*
  • Time Factors

Substances

  • Amyloid beta-Peptides
  • Antibodies