FUS-mediated blood–brain barrier disruption for delivering anti-Aβ antibodies in 5XFAD Alzheimer’s disease mice

Abstract

Purpose Amyloid-β (Aβ) 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-Aβ 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-Aβ therapeutics for clinical use.

Theranostics in Neurooncology: Heading Toward New Horizons

“…Technical implementations are diverse, ranging from implanted ultrasound transducer designs (17) appearing favorable for cost-effective repetitive openings of the supratentorial brain to fully MRI-guided transcranial (and thus noninvasive) devices (18), which appear favorable for deep-seated lesions in the brain stem or thalamus. Although this technology has not yet been used clinically in combination with a theranostic approach, preclinical studies demonstrating enhanced delivery of monoclonal antibodies to the parenchyma have shown considerable promise (19)(20)(21). Innovatively designed monoclonal antibodies also show promise to pass the physiologic BBB, such as single-domain antibodies and antibodies modified into a bispecific format (22,23).…”

Alzheimer's disease, a metabolic disorder: Clinical advances and basic model studies (Review)

“…The patient is unable to analyze, think and judge the events, and finds it difficult to deal with complex problems. Patients are unable to take care of themselves in daily life, making them and their family helpless over time (7,8). Although the exact process by which AD molecular cascades are triggered remains unclear, a series of epidemiological studies suggest that comorbid risk factors for metabolic disease are crucial in the pathogenesis of this disease (9)(10)(11).…”