Magnetothermal brain stimulation towards the rescue of beta-amyloid pathology

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种严重的神经退行性疾病，是痴呆的第一位病因。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， 淀粉样蛋白斑块的细胞外沉积有助于突触和神经元的丧失，导致认知功能障碍。 最终导致痴呆因此，对AD的疾病修饰疗法的研究一直是关注的焦点。 针对这种疾病的标志。目前，还没有经过证实的药物治疗来预防 一旦Aβ形成更大的聚集体，斑块就会被破坏，因此迫切需要开发一种创新的， 清除AD脑中Aβ斑块以治疗AD的替代策略。我们的长期目标是发展 一种微创、非药物干预，用于清除毒性Aβ斑块，治疗AD。 为此，在此，我们建议将磁热脑刺激作为一种非药理学策略， 靶向并清除毒性Aβ斑块，以挽救Aβ病理。这种方法的主要目的是 使用以下方法将高频交变磁场（AMF）的能量转换成热能 超顺磁性纳米粒子（MNP）作为换能器，可以触发热机械和生物 具有高时间和空间特异性信号。我们的核心假设是磁热脑刺激 通过热休克蛋白70（HSP 70）信号通路促进Aβ清除并改善AD患者的认知功能 个脑袋这一假设是基于我们发表的数据，证明了这种方法在靶向治疗中的可行性。 Aβ斑块中，我们发现MNP/AMF诱导的热机械能，在安全范围内应用， 脑组织的阈值足以将Aβ纤维破坏成较小的片段， 然后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， 针对人类小胶质细胞的刺激热能可以触发生物信号， 通过HSP 70依赖性方式激活以改善Aβ清除。为了证明我们的假设，我们建议 （1）建立用于小鼠脑功能的磁热脑刺激的阈值安全热剂量， (2)制定靶向磁热脑刺激策略，以改善Aβ的清除率 探讨磁热脑刺激影响Aβ的细胞机制 病理成功完成拟议的研究将提供如何申请的详细知识 磁热脑刺激作为针对AD中Aβ介导的病理学的创新治疗策略。

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.