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Nasal delivery of a CRMP2-derived CBD3 adenovirus improves cognitive function and pathology in APP/PS1 transgenic mice.
Molecular Brain ( IF 3.3 ) Pub Date : 2020-04-09 , DOI: 10.1186/s13041-020-00596-3
Baochang Qi 1 , Yu Yang 2 , Yingying Cheng 2 , Di Sun 3 , Xu Wang 2 , Rajesh Khanna 4, 5 , Weina Ju 2
Affiliation  

Calcium dysregulation is a key pathological event in Alzheimer's disease (AD). In studying approaches to mitigate this calcium overload, we identified the collapsin response mediator protein 2 (CRMP2), an axonal guidance protein that participates in synapse dynamics by interacting with and regulating activity of N-methyl-D-aspartate receptors (NMDARs). We further identified a 15 amino acid peptide from CRMP2 (designated CBD3, for calcium-binding domain 3), that reduced NMDAR-mediated Ca2+ influx in cultured neurons and post-synaptic NMDAR-mediated currents in cortical slices. Whether targeting CRMP2 could be therapeutically beneficial in AD is unknown. Here, using CBD3, we tested the utility of this approach. Employing the APP/PS1 mouse model of AD which demonstrates robust pathophysiology including Aβ1-42 deposition, altered tau levels, and diminished cognitive functions, we asked if overexpression of CBD3 could rescue these events. CBD3 was engineered into an adeno-associated vector and nasally delivered into APP/PS1 mice and then biochemical (immunohistochemistry, immunoblotting), cellular (TUNEL apoptosis assays), and behavioral (Morris water maze test) assessments were performed. APP/PS1 mice administered adeno-associated virus (AAV, serotype 2) harboring CBD3 demonstrated: (i) reduced levels of Aβ1-42 and phosphorylated-tau (a marker of AD progression), (ii) reduced apoptosis in the hippocampus, and (iii) reduced cognitive decline compared with APP/PS1 mice or APP/PS1 administered a control virus. These results provide an instructive example of utilizing a peptide-based approach to unravel protein-protein interactions that are necessary for AD pathology and demonstrate the therapeutic potential of CRMP2 as a novel protein player in AD.

中文翻译:


鼻腔递送 CRMP2 衍生的 CBD3 腺病毒可改善 APP/PS1 转基因小鼠的认知功能和病理学。



钙失调是阿尔茨海默病(AD)的一个关键病理事件。在研究缓解这种钙超载的方法时,我们发现了塌陷素反应介导蛋白 2 (CRMP2),这是一种轴突引导蛋白,通过与 N-甲基-D-天冬氨酸受体 (NMDAR) 相互作用并调节其活性来参与突触动力学。我们进一步从 CRMP2 中鉴定出一种 15 个氨基酸的肽(称为 CBD3,代表钙结合域 3),它可以减少培养神经元中 NMDAR 介导的 Ca2+ 流入以及皮质切片中 NMDAR 介导的突触后电流。靶向 CRMP2 是否对 AD 治疗有益尚不清楚。在这里,我们使用 CBD3 测试了这种方法的实用性。采用 AD 的 APP/PS1 小鼠模型显示了强大的病理生理学,包括 Aβ1-42 沉积、tau 水平改变和认知功能减弱,我们询问 CBD3 的过度表达是否可以挽救这些事件。 CBD3 被设计成腺相关载体,并经鼻递送至 APP/PS1 小鼠体内,然后进行生化(免疫组织化学、免疫印迹)、细胞(TUNEL 细胞凋亡测定)和行为(Morris 水迷宫测试)评估。给 APP/PS1 小鼠注射含有 CBD3 的腺相关病毒(AAV,血清型 2),结果显示:(i) Aβ1-42 和磷酸化 tau(AD 进展的标志物)水平降低,(ii) 海马细胞凋亡减少, (iii)与APP/PS1小鼠或施用对照病毒的APP/PS1小鼠相比,认知能力下降减少。这些结果提供了一个有启发性的例子,利用基于肽的方法来揭示 AD 病理学所必需的蛋白质-蛋白质相互作用,并证明了 CRMP2 作为 AD 中新型蛋白质参与者的治疗潜力。
更新日期:2020-04-09
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