Focused ultrasound with anti-pGlu3 Aβ enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells.
Focused ultrasound with anti-pGlu3 Aβ enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells.
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带有抗pGlu3Aβ的聚焦超声通过招募外周免疫细胞来提高阿尔茨海默病样小鼠的疗效。
DOI：
10.1016/j.jconrel.2021.06.037
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发表时间：
2021-08-10
期刊：
影响因子：
--
通讯作者：
Lemere CA
中科院分区：
文献类型：
--
作者：
Sun T;Shi Q;Zhang Y;Power C;Hoesch C;Antonelli S;Schroeder MK;Caldarone BJ;Taudte N;Schenk M;Hettmann T;Schilling S;McDannold NJ;Lemere CA
Pyroglutamate-3 amyloid-β (pGlu3 Aβ) is an N-terminally modified, pathogenic form of amyloid-β that is present in cerebral amyloid plaques and vascular deposits. Here, for the first time, wee used focused ultrasound (FUS) with microbubbles to enhance the intravenous delivery of an Fc-competent anti-pGlu3 Aβ monoclonal antibody, 07/2a mAb, across the blood brain barrier (BBB) in an attempt to improve Aβ removal and memory in aged APP/PS1dE9 mice, an Alzheimer’s disease-like model of amyloidogenesis. First, we demonstrated that bilateral hippocampal FUS-BBBD led to a 5.5-fold increase of 07/2a mAb in the brains of sonicated aged APP/PS1dE9 mice compared to non-sonicated mice 72 hours 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. APP/PS1dE9 mice given the combination treatment had reduced hippocampal plaque burden compared to PBS-treated APP/PS1dE9 mice. Furthermore, synaptic protein levels were higher in hippocampal synaptosomes from APP/PS1 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 Aβ 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.
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影响因子：
19.7
作者：
Hynynen, K;McDannold, N;Jolesz, FA
通讯作者：
Jolesz, FA
DOI：
10.3791/2270
发表时间：
2010-11-16
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Ippolito, Dominic M;Eroglu, Cagla
通讯作者：
Eroglu, Cagla
影响因子：
0.8
作者：
Leggio, Gian Marco;Torrisi, Sebastiano Alfio;Papaleo, Francesco
通讯作者：
Papaleo, Francesco
影响因子：
6.6
作者：
Chacko AM;Li C;Pryma DA;Brem S;Coukos G;Muzykantov V
通讯作者：
Muzykantov V
影响因子：
3
作者：
Kleinknecht, Karl R.;Bedenk, Benedikt T.;Wotjak, Carsten T.
通讯作者：
Wotjak, Carsten T.