Manipulating neural oscillations with non-invasive sensory stimulation for Alzheimer's disease intervention

通过非侵入性感觉刺激操纵神经振荡来干预阿尔茨海默病

• 批准号: 10228379
• 负责人: Li-Huei Tsai
• 金额: $ 76.17万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228379
• 关键词: Acetylcholinesterase Inhibitors; Acoustic Stimulation; Affect; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Antiepileptic Agents; Apolipoprotein E; Area; Astrocytes; Auditory; Auditory area; Behavior; Behavioral; Brain; Brain Diseases; Cells; Chemicals; Chronic; Cognitive; Combined Modality Therapy; Disease; Disease Progression; Epilepsy; Exhibits; FDA approved; Financial cost; Frequencies; Functional disorder; Genetic; Genetic Risk; Goals; Hippocampus (Brain); Human; Impaired cognition; Intervention; Knock-in Mouse; Length; Levetiracetam; Light; Maintenance; Medial; Memantine; Memory Loss; Microglia; Modality; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nature; Neurons; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Photic Stimulation; Population; Prefrontal Cortex; Reaction; Regimen; Reporting; Research; Response to stimulus physiology; Sensory; Stimulus; Symptoms; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Translating; Visual; Visual Cortex; aging population; cell type; cognitive function; donepezil; effective therapy; genetic risk factor; high risk; human subject; hyperphosphorylated tau; improved; loss of function; mouse model; multimodality; neural circuit; neuron loss; novel therapeutic intervention; optimal treatments; relating to nervous system; response; risk variant; sensory cortex; sensory stimulus; tau Proteins; treatment duration; β-amyloid burden

Alzheimer's disease (AD) is a debilitating brain disorder, with staggering human and financial cost in a rising aging population, and the complexity of the disease's underlying pathophysiology presents a major challenge in developing therapeutics. Recently, in an approach that we term Gamma ENtrainment Using Sensory stimuli (GENUS), we found that neural oscillations in the gamma frequency range (30-90 Hz) could be induced to impact pathology in AD mouse models by exposing them to flickering light at 40 Hz or 40 Hz train of auditory pure tone. We found that GENUS reduces amyloid burden and hyperphosphorylated tau in respective amyloid and tauopathy mouse models, as well as modifies microglia, astrocytes and vasculature. We also show that multimodal GENUS can be applied with simultaneous auditory and visual stimulation, and prolonged visual GENUS promises longer-lasting effects. Further, we report reduced AD pathology not only in the primary sensory cortex but also in the hippocampus and medial prefrontal cortex. Thus, the goal of our proposed research is to determine the efficacy and durability of multimodal GENUS and whether the beneficial effects of multimodal GENUS can be modulated by AD-related drug treatments and AD-risk carrier of APOE. To this end, we will systematically characterize the temporal profile of chronic multimodal GENUS (1 or 2 h/day) and determine the decay time of post-GENUS in amyloid and tau mouse models. We hypothesize that chronic multimodal GENUS for 6 weeks may impact different brain areas for longer periods. We will assess whether FDA approved drugs could modulate and enhance the longer-lasting decay time of post-GENUS after 6 weeks of multimodal GENUS. We will test an acetylcholinesterase inhibitor, an NMDA receptor antagonist, and an antiepileptic drug combined with chronic multimodal GENUS. APOE4 is the highest risk gene for sporadic AD, and ~40% of the global AD population carries at least one copy of APOE4. As such, we will investigate how APOE4 modifies GENUS response. Our recent studies show that GENUS impacts neurons, microglia, astrocytes and the vasculature, all of which are associated with APOE. We will use humanized APOE-knock in mice and APOE-knock in mice crossed with amyloid and tauopathy mouse models to determine whether APOE can modify the response to GENUS.

阿尔茨海默病(AD)是一种令人衰弱的大脑疾病，随着人类和经济成本的不断上升， 人口老龄化和疾病潜在病理生理学的复杂性是对 发展治疗学。最近，在一种我们称之为伽玛夹带的方法中，使用感觉刺激 (属)，我们发现伽马频率范围(30-90赫兹)的神经振荡可以诱导 通过将其暴露在40赫兹或40赫兹的听觉纯音序列闪烁的光中，对阿尔茨海默病小鼠模型进行病理学研究。 我们发现，Genus减少了淀粉样蛋白的负担和各自淀粉样蛋白中过度磷酸化的tau 治疗小鼠的自闭症，以及改善小胶质细胞、星形胶质细胞和血管系统。我们还表明， 多模式属可同时应用听觉和视觉刺激，并延长视觉 Genus有望产生更持久的影响。此外，我们报告了AD病理不仅在初级感觉上减少 但也存在于海马体和内侧前额叶皮质。因此，我们提出的研究目标是 确定多模式属的有效性和持久性，以及多模式属的有益效果 AD相关的药物治疗和APOE的AD风险携带者可以调节多峰属。至 为此，我们将系统地描述慢性多模式属(1或2小时/天)的时间分布。 并测定淀粉样蛋白和tau小鼠模型的后属衰变时间。我们假设慢性病 6周的多模式属可能会对不同的大脑区域产生更长的影响。我们将评估是否 FDA批准的药物可以调节和增强6周后较长时间的属后衰变时间 属于多峰属。我们将测试乙酰胆碱酯酶抑制剂、NMDA受体拮抗剂和 抗癫痫药联合慢性多峰药属。载脂蛋白E4是散发性阿尔茨海默病的高危基因， 全球约40%的AD患者至少携带一份APOE4基因。因此，我们将调查如何 ApoE4修饰属反应。我们最近的研究表明，属影响神经元、小胶质细胞、星形胶质细胞 以及血管系统，所有这些都与APOE有关。我们将使用人源化的APOE敲击小鼠和 APOE敲击与淀粉样蛋白和肌萎缩侧索硬化症小鼠模型杂交以确定APOE是否可以修改 对属的反应。