Ultrasound-targeted microbubbles destruction assists dual delivery of beta-amyloid antibody and neural stem cells to restore neural function in transgenic mice of Alzheimer's disease

Objectives To explore the feasibility, efficacy, and safety of ultrasound-targeted microbubbles destruction (UTMD) assisted dual delivery of beta-amyloid (A beta) antibody loaded by microbubbles (MBA beta) and neural stem cells (NSCs) on Alzheimer's disease (AD). Methods Twenty-seven APP/PS1 double transgenic mice (Tg mice) and 33 wild-type mice were used. Wild-type mice were insonated by diagnostic ultrasound with microbubbles (MB) for 5 min to observe the blood brain barrier (BBB) opening. The survival situation of engrafted NSCs crossing the opened BBB mediated by UTMD in Tg mice was evaluated by in vivo imaging system. We further explored the combination therapy effects of UTMD mediated A beta antibody and NSCs dual delivery. Tg mice in each group were exposed to diagnostic ultrasound for 5 min once a week for four times, with MB, MBA beta, and/or NSCs administration according to groups. Cognition and memory functions were explored by Morris water maze test, A beta plaques deposition was evaluated by immunohistochemical, and brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN) expression were detected by western blot and immunofluorescence. Results BBB was opened mediated by diagnostic ultrasound with MB, and the duration of opening was about 10 h. The transplanted NSCs survived in Tg mice for no more than 72 h. Compared with control group, the Tg mice in combined delivery of NSCs and A beta antibody by UTMD group improved memory function and spatial learning with shorter latency to find the platform, longer distance traveled, and longer time spent in targeted quadrant, and more crossing times (p < 0.05). Besides, the combination delivery group promoted the clearance of A beta plaques compared with control group both in hippocampus (p < 0.01) and cortex (p < 0.05). Moreover, the expression of BDNF in combination delivery group was significantly higher than that in control group and ultrasound-mediated MB group (p < 0.05). No significant change of SYN was observed in each group. Conclusion UTMD assisted dual delivery of A beta antibody and NSCs crossing the BBB into AD mice brain could help to clear A beta plaques, increase the expression of BDNF, and restore the impaired neural function. This finding may offer potential insight into treatment of AD.

Automated summary

This study explored the feasibility, efficacy, and safety of ultrasound-targeted microbubbles destruction-assisted dual delivery of beta-amyloid antibody and neural stem cells for Alzheimer's disease. The results showed that the dual delivery treatment improved memory and spatial learning, promoted Aβ plaques clearance, and increased BDNF expression, providing potential insight for AD treatment.