Ultrasound Mediated Microbubbles Destruction Assists Dual Delivery of Beta-amyloid Antibody and NSCs to Restore Neural Function in Transgenic Mice of Alzheimer’s Disease

Abstract

Background : To explore the feasibility, efficacy and safety of ultrasound mediated microbubbles destruction（UMMD） assisted dual delivery of β-amyloid antibody loaded by microbubbles (MB Aβ ) and neural stem cells (NSCs) on Alzheimer’s disease（AD）. Methods : 27 APP/PS1 double transgenic mice and 33 wild-type mice were used. The dual delivery of β-amyloid antibody and NSCs group (US+MB Aβ +NSCs), single delivery of β-amyloid antibody group (US+MB Aβ ), US+MB group, Control group and Wild group, were involved in the experiment. MB Aβ or MB were injected via the tail vein, followed by NSCs or saline administration and exposed to ultrasound once a week for four times. The survival of NSCs was detected with the in vivo imaging method. Mice in each group were used for behavioral function evaluation and the pathology tests. Brain samples were used to detect β-amyloid deposition, BDNF and synaptophysin expression. Results : BBB was opened by UMMD with an opening time about 10 h. The transplanted NSCs survived in AD brain for no more than 72 h. The learning and spatial memory function was significantly improved in the US+MB Aβ +NSCs group, US+MB Aβ group came second. Immunochemistry results showed amyloid plaques reduction in the US+MB Aβ +NSCs group at the cortex and hippocampus. Higher level of BDNF was demonstrated in the US+MB Aβ +NSCs group than the US+MB Aβ group and the Control group with Western Blot and immunofluorescence examination, but synaptophysin remained no significant changes. Conclusions : UMMD assisted combined delivery of β-amyloid antibody and NSCs to AD mice brain can help to clear the Aβ peptide, increase BDNF level and restore the impaired neural function, which was superior to β-amyloid antibody delivery group. Therefore, the combined targeted delivery assisted by UMMD strategy may be a promising and safe method on treating AD.