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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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) 是一种使人衰弱的脑部疾病，其造成的人力和财力成本不断上升人口老龄化以及该疾病潜在病理生理学的复杂性提出了重大挑战开发治疗方法。最近，我们采用一种称为“使用感觉刺激进行伽玛训练”的方法（GENUS），我们发现伽马频率范围（30-90 Hz）中的神经振荡可以引起影响通过将 AD 小鼠模型暴露在 40 Hz 或 40 Hz 听觉纯音序列的闪烁光下，研究 AD 小鼠模型的病理学。我们发现 GENUS 减少了淀粉样蛋白的负担以及淀粉样蛋白和淀粉样蛋白中 tau 蛋白的过度磷酸化。 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。我们还表明多模式 GENUS 可以同时应用听觉和视觉刺激，以及长时间的视觉刺激 GENUS 承诺具有更持久的效果。此外，我们报告 AD 病理的减少不仅在初级感觉方面皮层还存在于海马体和内侧前额叶皮层。因此，我们提出的研究目标是确定多模式 GENUS 的功效和持久性以及是否有有益作用多模式 GENUS 可以通过 AD 相关药物治疗和 APOE 的 AD 风险携带者进行调节。到为此，我们将系统地描述慢性多模式属的时间概况（1 或 2 小时/天）并确定淀粉样蛋白和 tau 小鼠模型中 GENUS 后的衰减时间。我们假设慢性持续 6 周的多模式 GENUS 可能会更长时间地影响不同的大脑区域。我们将评估是否 FDA 批准的药物可以调节和增强 6 周后 GENUS 后更持久的衰减时间属于多模式属。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物联合慢性多模式GENUS。 APOE4 是散发性 AD 风险最高的基因，全球约 40% 的 AD 人群至少携带一份 APOE4 拷贝。因此，我们将研究如何 APOE4 修改 GENUS 响应。我们最近的研究表明 GENUS 影响神经元、小胶质细胞、星形胶质细胞和脉管系统，所有这些都与 APOE 相关。我们将在小鼠中使用人源化 APOE 敲入对与淀粉样蛋白和 tau 蛋白病小鼠模型杂交的小鼠进行 APOE 敲除，以确定 APOE 是否可以修饰对 GENUS 的回应。