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

Jessica F Jordão,Carlos A Ayala-Grosso,Kullervo Hynynen,Yuexi Huang,Rajiv Chopra,Joanne Mclaurin,Isabelle Aubert,Kelly Markham,Joseph El Khoury

doi:10.1371/journal.pone.0010549

Abstract

Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Aβ), which circulate in the bloodstream and remove Aβ 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 Aβ 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 Aβ plaques in targeted cortical areas. Four days post-treatment, Aβ 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.

Highlights

Evidence of amyloid-beta peptide (Ab) toxicity, including in the brain of people with Alzheimer’s disease (AD) [11], reinforces the need to improve current anti-Ab treatment
The entry of gadolinium into the right, targeted hemisphere was observed within 5–10 min following magnetic resonance imaging-guided FUS (MRIgFUS) in the presence and absence of anti-Ab antibody, BAM-10, confirming a localized disruption of the blood-brain barrier (BBB) (Fig. 1B–D)
We evaluated whether MRIgFUS could deliver a low peripheral dose of BAM-10 into the brain

Summary

Introduction

Evidence of Ab toxicity, including in the brain of people with AD [11], reinforces the need to improve current anti-Ab treatment. Current treatments in AD patients require the long-term administration of high doses of antibodies against Ab in the bloodstream in order to remove Ab plaques from the brain of AD patients [12,13]. In mouse models of AD, cognitive improvement following immunotherapy was obtained with intravenous or intraperitoneal administration of high doses of 500 mg of anti-Ab antibodies [14,15,16]. Considering that only up to 0.1% of anti-Ab antibodies administered peripherally can reach the brain [17], most, administered antibody remains in the bloodstream. Targeted delivery of antibodies in the brain allows for a greater proportion of anti-Ab antibodies to reach the affected brain region, which may result in better treatment efficacy in AD patients

Objectives

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Conclusion