聚焦超声传递选择性 TrkA 激动剂可挽救阿尔茨海默病小鼠模型中的胆碱能功能。

Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer's disease.

机构信息

Hurvitz Brain Sciences Research Program, Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.

Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

出版信息

Sci Adv. 2020 Jan 22;6(4):eaax6646. doi: 10.1126/sciadv.aax6646. eCollection 2020 Jan.

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 p75 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 p75, 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.

胆碱能神经元的退化是阿尔茨海默病（AD）的一个显著特征。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。然而，在 AD 病理存在的情况下，NGF 相关治疗尚未发挥其再生潜力。我们提出，刺激 TrkA 受体而不激活 p75 是治疗效果的关键。支持这一假设，选择性 TrkA 激动剂 D3 挽救了 TgCRND8 小鼠中的神经营养因子信号，而与 TrkA 和 p75 都相互作用的 NGF 则没有。D3 通过静脉内给予，并使用 MRI 引导的聚焦超声（MRIgFUS）介导的血脑屏障（BBB）通透性非侵入性地递送至基底前脑，激活了 TrkA 相关的信号级联，并增强了胆碱能神经传递。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。针对 TrkA 的神经保护剂与 MRIgFUS BBB 调节相结合，代表了一种有前途的策略，可以对抗 AD 中的神经退行性变。