title: Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta 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 (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.
authors.affiliation: Brain Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Jordão
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Ayala-Grosso
authors.forename: Kelly
authors.initials: K
authors.lastname: Markham
authors.forename: Yuexi
authors.initials: Y
authors.lastname: Huang
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: JoAnne
authors.initials: J
authors.lastname: McLaurin
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aubert
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000473:pathology; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D004453:Echoencephalography; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D010539:Permeability; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000473:pathology*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies