Focused Ultrasound-Induced Blood-Brain Barrier Opening Enhances GSK-3 Inhibitor Delivery for Amyloid-Beta Plaque Reduction

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that is the leading cause of age-related dementia. Currently, therapeutic agent delivery to the CNS is a valued approach for AD therapy. Unfortunately, the CNS penetration is greatly hampered by the blood-brain barrier (BBB). Focused-ultrasound (FUS) has been demonstrated to temporally open the BBB, thus promoting therapeutic agent delivery to the CNS. Recently, the BBB opening procedure was further reported to clear the deposited Aβ plaque due to microglia activation. In this study, we aimed to evaluate whether the use of FUS-induced BBB opening to enhance GSK-3 inhibitor delivery, which would bring additive effect of Aβ plaque clearance by FUS with the reduction of Aβ plaque synthesis by GSK-3 inhibitor in an AD mice model. FUS-induced BBB opening on APPswe/PSEN1-dE9 transgenic mice was performed unilaterally, with the contralateral hemisphere serving as a reference. GSK-3 level was confirmed by immunohistochemistry (IHC) and autoradiography (ARG) was also conducted to quantitatively confirm the Aβ plaque reduction. Results from IHC showed GSK-3 inhibitor effectively reduced GSK-3 activity up to 61.3% with the addition of FUS-BBB opening and confirming the proposed therapeutic route. ARG also showed significant Aβ-plaque reduction up to 31.5%. This study reveals the therapeutic potentials of ultrasound to AD treatment, and may provide a useful strategy for neurodegenerative disease treatment.