FUS-mediated blood-brain barrier disruption for delivering anti-Aß antibodies in 5XFAD Alzheimer's disease mice.

ABSTRACT

PURPOSE: Amyloid-ß (Aß) peptides, the main component of amyloid plaques found in the Alzheimer's disease (AD) brain, are implicated in its pathogenesis, and are considered a key target in AD therapeutics. We herein propose a reliable strategy for non-invasively delivering a specific anti-Aß antibody in a mouse model of AD by microbubbles-enhanced Focused Ultrasound (FUS)-mediated Blood-brain barrier disruption (BBBD), using a simple single stage MR-compatible positioning device. METHODS: The initial experimental work involved wild-type mice and was devoted to selecting the sonication protocol for efficient and safe BBBD. Pulsed FUS was applied using a single-element FUS transducer of 1 MHz (80 mm radius of curvature and 50 mm diameter). The success and extent of BBBD were assessed by Evans Blue extravasation and brain damage by hematoxylin and eosin staining. 5XFAD mice were divided into different subgroups; control (n = 1), FUS + MBs alone (n = 5), antibody alone (n = 5), and FUS + antibody combined (n = 10). The changes in antibody deposition among groups were determined by immunohistochemistry. RESULTS: It was confirmed that the antibody could not normally enter the brain parenchyma. A single treatment with MBs-enhanced pulsed FUS using the optimized protocol (1 MHz, 0.5 MPa in-situ pressure, 10 ms bursts, 1% duty factor, 100 s duration) transiently disrupted the BBB allowing for non-invasive antibody delivery to amyloid plaques within the sonicated brain regions. This was consistently reproduced in ten mice. CONCLUSION: These preliminary findings should be confirmed by longer-term studies examining the antibody effects on plaque clearance and cognitive benefit to hold promise for developing disease-modifying anti-Aß therapeutics for clinical use.