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.

阿尔茨海默氏病（AD）是一种使人衰弱的脑部疾病，随着人类和经济成本的不断上升， 人口老龄化，以及疾病的潜在病理生理学的复杂性提出了一个重大挑战， 开发治疗方法。最近，在一种方法中，我们称之为使用感官刺激的伽马夹带 （GENUS），我们发现伽马频率范围（30-90 Hz）的神经振荡可以被诱导产生影响 通过将AD小鼠模型暴露于40 Hz或40 Hz听觉纯音串的闪烁光中来观察AD小鼠模型的病理学。 我们发现GENUS减少了淀粉样蛋白负荷和相应淀粉样蛋白中过度磷酸化的tau蛋白， tau蛋白病小鼠模型以及修饰小胶质细胞、星形胶质细胞和脉管系统。我们也证明了 多模式GENUS可以同时应用听觉和视觉刺激， GENUS承诺更持久的效果。此外，我们报告减少AD病理不仅在初级感觉 大脑皮层，海马体和内侧前额叶皮层也是如此。因此，我们提出的研究目标是 确定多模式GENUS的有效性和持久性，以及 多模式GENUS可通过AD相关药物治疗和AD风险携带者APOE调节。到 为此，我们将系统地描述慢性多模态GENUS（1或2小时/天）的时间特征 并确定淀粉样蛋白和tau小鼠模型中post-GENUS的衰减时间。我们假设慢性的 6周的多模式GENUS可能会影响不同的大脑区域更长的时间。我们将评估是否 FDA批准的药物可以在6周后调节和增强post-GENUS的持久衰减时间 多模式基因我们将测试一种乙酰胆碱酯酶抑制剂，一种NMDA受体拮抗剂， 抗癫痫药联合慢性多模式GENUS。APOE 4是散发性AD的最高风险基因， 全球约40%的AD人群携带至少一个APOE 4拷贝。因此，我们将研究如何 APOE 4修饰GENUS反应。我们最近的研究表明GENUS影响神经元、小胶质细胞、星形胶质细胞 和血管系统，所有这些都与载脂蛋白E有关。我们将在小鼠中使用人源化APOE敲除， 在与淀粉样蛋白和tau蛋白病小鼠模型杂交的小鼠中进行APOE敲除，以确定APOE是否可以修饰 对GENUS的回应