Focused ultrasound with anti-pGlu3 Aβ enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells

JOURNAL OF CONTROLLED RELEASE

卷:336

Article

Sun, Tao^1,3  Shi, Qiaoqiao^2,3  Zhang, Yongzhi^1,3  Power, Chanikarn^1,3  Hoesch, Camilla²  Antonelli, Shawna²  Schroeder, Maren K.²  Caldarone, Barbara J.⁴  Taudte, Nadine⁵  Schenk, Mathias⁵  Hettmann, Thore⁶  Schilling, Stephan^5,6,7  McDannold, Nathan J.^1,3  Lemere, Cynthia A.^2,3 

[1] Brigham & Womens Hosp, Dept Radiol, Focused Ultrasound Lab, 75 Francis St, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Dept Neurol, Ann Romney Ctr Neurol Dis, 75 Francis St, Boston, MA 02115 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

[4] Harvard Med Sch, Mouse Behav Core, Boston, MA 02115 USA

[5] Fraunhofer Inst Cell Therapy & Immunol, Dept Mol Drug Biochem & Therapy, Halle, Saale, Germany

[6] Vivoryon Therapeut AG, Halle, Saale, Germany

[7] Anhalt Univ Appl Sci, Kothen, Germany

关键词: Focused ultrasound;    Blood brain barrier;    Drug delivery;    Pyroglutamate-3 amyloid-beta;    Alzheimer's disease;   

DOI  :  10.1016/j.jconrel.2021.06.037

来源: Elsevier

【 摘 要 】

Pyroglutamate-3 amyloid-beta (pGlu3 A beta) is an N-terminally modified, pathogenic form of amyloid-beta that is present in cerebral amyloid plaques and vascular deposits. Here, we used focused ultrasound (FUS) with microbubbles to enhance the intravenous delivery of an Fc-competent anti-pGlu3 A beta monoclonal antibody, 07/2a mAb, across the blood brain barrier (BBB) in an attempt to improve A beta removal and memory in aged APP/PS1dE9 mice, an Alzheimer's disease (AD)-like model of amyloidogenesis. First, we demonstrated that bilateral hippocampal FUS-BBB disruption (FUS-BBBD) led to a 5.5-fold increase of 07/2a mAb delivery to the brains compared to non-sonicated mice 72 h following a single treatment. Then, we determined that three weekly treatments with 07/2a mAb alone improved spatial learning and memory in aged, plaque-rich APP/PS1dE9 mice, and that this improvement occurred faster and in a higher percentage of animals when combined with FUS-BBBD. Mice given the combination treatment had reduced hippocampal plaque burden compared to PBS-treated controls. Furthermore, synaptic protein levels were higher in hippocampal synaptosomes from mice given the combination treatment compared to sham controls, and there were more CA3 synaptic puncta labeled in the APP/PS1dE9 mice given the combination treatment compared to those given mAb alone. Plaque-associated microglia were present in the hippocampi of APP/PS1dE9 mice treated with 07/2a mAb with and without FUS-BBBD. However, we discovered that plaque-associated Ly6G+ monocytes were only present in the hippocampi of APP/PS1dE9 mice that were given FUS-BBBD alone or even more so, the combination treatment. Lastly, FUS-BBBD did not increase the incidence of microhemorrhage in mice with or without 07/2a mAb treatment. Our findings suggest that FUS is a useful tool to enhance delivery and efficacy of an anti-pGlu3 A beta mAb for immunotherapy either via an additive effect or an independent mechanism. We revealed a potential novel mechanism wherein the combination of 07/2a mAb with FUS-BBBD led to greater monocyte infiltration and recruitment to plaques in this AD-like model. Overall, these effects resulted in greater plaque removal, sparing of synapses and improved cognitive function without causing overt damage, suggesting the possibility of FUS-BBBD as a noninvasive method to increase the therapeutic efficacy of drugs or biologics in AD patients.

【 授权许可】

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