Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta 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 (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.
Jordão
Jessica F
JF
Brain Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
Ayala-Grosso
Carlos A
CA
Markham
Kelly
K
Huang
Yuexi
Y
Chopra
Rajiv
R
McLaurin
JoAnne
J
Hynynen
Kullervo
K
Aubert
Isabelle
I
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
D016229:Amyloid beta-Peptides; D000906:Antibodies