Brain Penetrating Bifunctional Erythropoietin-Transferrin Receptor Antibody Fusion Protein for Alzheimer's Disease.
Brain Penetrating Bifunctional Erythropoietin-Transferrin Receptor Antibody Fusion Protein for Alzheimer's Disease.
复制标题
DOI：
10.1021/acs.molpharmaceut.8b00594
复制
发表时间：
2018-11-05
影响因子：
4.9
通讯作者：
Sumbria RK
中科院分区：
文献类型：
--
作者：
Chang R;Al Maghribi A;Vanderpoel V;Vasilevko V;Cribbs DH;Boado R;Pardridge WM;Sumbria RK
促红细胞生成素（EPO）是造血所必需的糖蛋白细胞因子，在阿尔茨海默病（AD）啮齿动物模型中具有神经保护作用。然而，由于低血脑屏障（BBB）穿透性，需要高治疗剂量或侵入性途径的EPO施用以实现有效的脑浓度，并且高EPO剂量导致造血副作用。这些障碍可以通过将EPO与靶向转铁蛋白受体的嵌合单克隆抗体（cTfRMAb）融合来工程化BBB可穿透的EPO类似物来克服，所述EPO类似物通过将EPO经由经血管途径运送到大脑中而充当分子特洛伊木马。在目前的研究中，我们研究了BBB可穿透的EPO类似物在AD双转基因小鼠模型中对AD病理学的影响。5.5用盐水（n=10）或BBB可穿透的EPO（n=10）腹膜内处理月龄雄性APP swe PSEN 1dE 9（APP/PS1）转基因小鼠3天/周，持续8周，与用盐水以相同方案处理的同龄C57 BL/6 J野生型小鼠（n=8）相比。在给药开始后9周，通过旷场和Y迷宫试验评估探索和空间记忆，处死小鼠，并评价脑的Aβ肽负荷、突触丢失、BBB破坏、小胶质细胞活化和微血管扩张。与APP/PS1生理盐水对照组相比，用BBB可穿透的cTfRMAb-EPO融合蛋白处理的APP/PS1小鼠具有显著较低的皮质和海马Aβ肽数量（p <0.05）和免疫阳性面积（p<0.05），海马突触丢失（p<0.05）和皮质小胶质细胞活化（p<0.001）减少，以及改善的空间记忆（p<0.05）。穿透BBB的EPO与微出血的发生无关。cTfRMAb-EPO融合蛋白通过靶向AD发病机制和进展的多个靶点（Aβ负荷、突触丢失、小胶质细胞活化）并改善AD的APP/PS1小鼠模型中的空间记忆来提供治疗益处。
Erythropoietin (EPO), a glycoprotein cytokine essential to hematopoiesis, has neuroprotective effects in rodent models of Alzheimer’s disease (AD). However, high therapeutic doses or invasive routes of administration of EPO are required to achieve effective brain concentrations due to low blood-brain barrier (BBB) penetrability, and high EPO doses result in hematopoietic side effects. These obstacles can be overcome by engineering a BBB-penetrable analog of EPO, which is rapidly cleared from the blood, by fusing EPO to a chimeric monoclonal antibody targeting the transferrin receptor (cTfRMAb), which acts as a molecular Trojan horse to ferry the EPO into the brain via the transvascular route. In the current study, we investigated the effects of the BBB-penetrable analog of EPO on AD pathology in a double transgenic mouse model of AD. 5.5 month old male APPswe PSEN1dE9 (APP/PS1) transgenic mice were treated with saline (n=10), or the BBB-penetrable EPO (n=10) 3 days/week intraperitoneally for 8 weeks, compared to same-aged C57BL/6J wild-type mice treated with saline (n=8) with identical regiment. At 9 weeks following treatment initiation, exploration and spatial memory were assessed with the open-field and Y-maze test, mice were sacrificed, and brains were evaluated for Aβ peptide load, synaptic loss, BBB disruption, microglial activation and microhemorrhages. APP/PS1 mice treated with the BBB-penetrable cTfRMAb-EPO fusion protein had significantly lower cortical and hippocampal Aβ peptide number (p<0.05) and immune-positive area (p<0.05), a decrease in hippocampal synaptic loss (p<0.05) and cortical microglial activation (p<0.001), and improved spatial memory (p<0.05) compared with APP/PS1 saline controls. BBB-penetrating EPO was not associated with microhemorrhage development. The cTfRMAb-EPO fusion protein offers therapeutic benefits by targeting multiple targets of AD pathogenesis and progression (Aβ load, synaptic loss, microglial activation) and improving spatial memory in the APP/PS1 mouse model of AD.
登录
查看更多内容
影响因子：
3.8
作者：
Boado, Ruben J.;Zhang, Yun;Wang, Yuntao;Pardridge, William M.
通讯作者：
Pardridge, William M.
影响因子：
5
作者：
Banks, WA;Jumbe, NL;Heatherington, AC
通讯作者：
Heatherington, AC
影响因子：
1
作者：
Arabpoor Z;Hamidi G;Rashidi B;Shabrang M;Alaei H;Sharifi MR;Salami M;Dolatabadi HR;Reisi P
通讯作者：
Reisi P
影响因子：
3
作者：
Jirkof, Paulin
通讯作者：
Jirkof, Paulin
影响因子：
2.5
作者：
Genc, S;Kuralay, F;Gure, A
通讯作者：
Gure, A