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Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer's disease.
Science Advances ( IF 13.6 ) Pub Date : 2020-01-22 , DOI: 10.1126/sciadv.aax6646
K Xhima 1, 2 , K Markham-Coultes 1 , H Nedev 3, 4 , S Heinen 1 , H U Saragovi 3, 4 , K Hynynen 5, 6 , I Aubert 1, 2
Affiliation  

The degeneration of cholinergic neurons is a prominent feature of Alzheimer's disease (AD). In animal models of injury and aging, nerve growth factor (NGF) enhances cholinergic cell survival and function, contributing to improved memory. In the presence of AD pathology, however, NGF-related therapeutics have yet to fulfill their regenerative potential. We propose that stimulating the TrkA receptor, without p75NTR activation, is key for therapeutic efficacy. Supporting this hypothesis, the selective TrkA agonist D3 rescued neurotrophin signaling in TgCRND8 mice, whereas NGF, interacting with both TrkA and p75NTR, did not. D3, delivered intravenously and noninvasively to the basal forebrain using MRI-guided focused ultrasound (MRIgFUS)-mediated blood-brain barrier (BBB) permeability activated TrkA-related signaling cascades and enhanced cholinergic neurotransmission. Recent clinical trials support the safety and feasibility of MRIgFUS BBB modulation in AD patients. Neuroprotective agents targeting TrkA, combined with MRIgFUS BBB modulation, represent a promising strategy to counter neurodegeneration in AD.

中文翻译:

选择性TrkA激动剂的聚焦超声递送可以挽救阿尔茨海默氏病小鼠模型中的胆碱能功能。

胆碱能神经元的变性是阿尔茨海默氏病(AD)的突出特征。在损伤和衰老的动物模型中,神经生长因子(NGF)增强了胆碱能细胞的存活和功能,有助于改善记忆力。然而,在存在AD病理学的情况下,与NGF相关的疗法尚未实现其再生潜力。我们建议,在没有p75NTR激活的情况下刺激TrkA受体是治疗功效的关键。支持该假设的是,选择性TrkA激动剂D3可以挽救TgCRND8小鼠的神经营养蛋白信号传导,而与TrkA和p75NTR相互作用的NGF则不能。D3 使用MRI引导的聚焦超声(MRIgFUS)介导的血脑屏障(BBB)渗透性静脉内和无创地递送至基底前脑,激活TrkA相关的信号级联反应并增强胆碱能神经传递。最近的临床试验支持MRIgFUS BBB调节在AD患者中的安全性和可行性。靶向TrkA的神经保护剂与MRIgFUS BBB调节相结合,代表了一种有前途的抗击AD神经变性的策略。
更新日期:2020-01-23
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