Magnetothermal brain stimulation towards the rescue of beta-amyloid pathology

项目摘要 阿尔茨海默病(AD)是一种毁灭性的神经退行性疾病，是痴呆症的首要原因。许多 一系列遗传和生化证据强烈强调了β-淀粉样蛋白(Aβ)的病理作用，其中 淀粉样蛋白斑块的细胞外沉积导致突触和神经元的丧失，导致认知障碍 缺陷，最终导致痴呆症。因此，寻找治疗AD的疾病修饰疗法一直是人们关注的焦点 关于瞄准这种疾病的标志。目前，还没有被证明有效的药物治疗来预防 斑块一旦Aβ形成更大的聚集体，因此迫切需要开发一种创新和 清除AD大脑中Aβ斑块用于治疗AD的替代策略。我们的长远目标是发展 一种微创、非药物干预措施，用于去除治疗AD的有毒Aβ斑块。 为此，我们建议将磁热脑刺激作为一种非药理学策略应用于 靶向并清除有毒的Aβ斑块以挽救Aβ病理。这种方法的基本原理是 将高频交变磁场(AMF)的能量转化为热能 超顺磁性纳米颗粒(MNPs)作为一种可以触发热机械和生物的换能器 信号具有高度的时间和空间特异性。我们的中心假设是磁热脑刺激 在AD中通过热休克蛋白70信号促进β清除和改善认知功能 大脑。这一假设是基于我们公布的数据，证明了这种方法在目标定位方面的可行性。 Aβ斑块，其中我们显示了MnP/AMF诱导的热机械能，在安全的 脑组织的阈值，足以将Aβ纤维分解成更小的片段，这些片段 然后很容易被小胶质细胞吞噬和清除。在我们的初步研究中，我们还发现远程 定向到人类小胶质细胞的受激热能可以触发生物信号，使小胶质细胞 通过热休克蛋白70依赖的方式激活以改善Aβ清除。为了证明我们的假设，我们建议 为了(1)确定磁热脑刺激对小鼠脑功能的阈值安全热剂量， (2)制定针对性的磁热脑刺激策略，以提高β的清除率 以及(3)研究磁热脑刺激影响β的细胞机制 病理学。拟议研究的成功完成将提供如何应用的详细知识 磁热脑刺激作为对抗β介导的AD病理的一种创新治疗策略。

Project Summary Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the first cause of dementia. Many lines of genetic and biochemical evidence strongly highlight a pathological role of beta-amyloid (Aβ) where extracellular deposition of amyloid plaques contributes to the loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. As such, the search for disease-modifying therapies for AD has been focused on targeting the hallmark of the disease. Currently, there is no proven pharmacological treatment for preventing the plaques once Aβ forms a larger aggregate and thus there is an urgent need to develop an innovative and alternative strategy to clear Aβ plaques in the AD brain for the treatment of AD. Our long-term goal is to develop a minimally invasive, non-pharmacological intervention to remove toxic Aβ plaques towards the treatment of AD. To this end, herein we propose to apply magnetothermal brain stimulation as a non-pharmacological strategy to target and remove toxic Aβ plaques towards the rescue of Aβ pathology. The principal of this approach is to translate the energy of the high frequency alternating magnetic field (AMF) into thermal energy using superparamagnetic nanoparticles (MNPs) as a transducer that can trigger thermo-mechanical and biological signal with high temporal and spatial specificity. Our central hypothesis is that magnetothermal brain stimulation facilitates Aβ clearance and improves cognitive function via heat shock protein 70 (HSP70) signaling in the AD brain. This hypothesis is based on our published data demonstrating the feasibility of this approach in targeting Aβ plaques where we showed that MNP/AMF-induced thermo-mechanical energy, applied within a safe threshold for brain tissue, was sufficient to direct the disruption of Aβ fibrils into smaller fragments, which were then readily phagocytosed and cleared by microglia. In our preliminary study, we also found that the remotely stimulated thermal energy directed to human microglia could trigger biological signal that shifts microglial activation towards improved Aβ clearance via HSP70-dependent manner. To prove our hypothesis, we propose to (1) establish the threshold safe thermal dose of magnetothermal brain stimulation for brain functioning in mice, (2) develop strategies for targeted magnetothermal brain stimulation towards the improved clearance of Aβ plaques, and (3) investigate the cellular mechanism by which magnetothermal brain stimulation influences Aβ pathology. The successful completion of the proposed study will provide detailed knowledge of how to apply magnetothermal brain stimulation as an innovative therapeutic strategy against Aβ-mediated pathology in AD.