Gamma Sensory Flicker as an Early Intervention for Alzheimer’s Disease: Mechanisms and Protective Effects

伽马感觉闪烁作为阿尔茨海默病的早期干预措施：机制和保护作用

• 批准号: 10745092
• 负责人: Annabelle Catherine Singer
• 金额: $ 196.71万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745092
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloidosis; Animals; Anti-Inflammatory Agents; Behavior; Biological Assay; Brain; Data; Disease; Early Intervention; Environment; Enzyme-Linked Immunosorbent Assay; Frequencies; Funding; Future; Gene Expression Profile; Genes; Genetic Risk; Genetic Transcription; Goals; Hippocampus; Human; Immune; Immunologic Memory; Impairment; Inflammation; Inflammatory; Knock-in Mouse; Learning; Light; Mediating; Memory; Memory Loss; Memory impairment; Methods; Microglia; Molecular; Mus; NF-kappa B; Neurons; Onset of illness; Pathogenesis; Pathology; Phenotype; Play; Populations at Risk; Positioning Attribute; Pre-Clinical Model; Prefrontal Cortex; Process; Proteins; Proteomics; Research; Rewards; RiboTag; Role; Senile Plaques; Sensory; Signal Transduction; Symptoms; Testing; Work; amyloid pathology; apolipoprotein E-4; beta amyloid pathology; cell type; cytokine; experience; genetic manipulation; genetic risk factor; human tissue; immune function; improved; innovation; memory process; millisecond; mouse model; neural; neural stimulation; neurotransmission; noninvasive brain stimulation; novel strategies; novel therapeutic intervention; pharmacologic; pre-clinical; prophylactic; protective effect; recruit; resilience; response; safety and feasibility; small hairpin RNA; sound; transcriptomics; virtual environment

Gamma Sensory Flicker as an Early Intervention for Alzheimer's Disease: Mechanisms and Protective Effects Alzheimer's disease (AD) requires a new therapeutic approach to intervene prior to or early in the disease. In the previous funding period, the PI and team discovered that gamma, or 40Hz, sensory flicker (lights and sounds turning on and off with millisecond precision) has beneficial effects in mouse models of Alzheimer's pathology at symptomatic stages. Gamma flicker drove gamma neural activity, reduced amyloid plaques, recruited microglia to engulf amyloid beta (Aβ), and restored memory behavior in mice with Aβ pathology. This proposal marks the exciting shift of this research to intervene in AD during the preclinical stages prior to plaque accumulation and the onset of memory deficits. Microglia and cytokines play a disease modifying role in AD and affect network function, with potential damaging or beneficial effects. Recent research, from our team and others, reveals protective immune gene and protein signatures in early AD pathogenesis. The goal of this proposal is to determine how flicker stimulation affects protective immune function in preclinical AD stages to improve neural signatures of memory and to elucidate the mechanisms of these effects. Using cutting edge transcriptomic and proteomic analyses and large-scale neural recordings, we will determine the effects of flicker on microglia phenotypes and neural signatures of memory. Using pharmacological and genetic manipulations, we will determine the causal role of microglia and microglial signaling in mediating flicker's effects on microglia phenotype and network function. We will determine if flicker-induced microglia gene transcription overlaps with recently defined human anti-inflammatory microglia markers present in early AD, using our teams' discoveries from cutting edge cell-type specific analysis of human tissue. Aim 1 will define the effects of flicker on microglia phenotype at preclinical stages, the molecular mechanisms involved, and the human-relevant transcriptional effects. Aim 2 will establish how preclinical flicker affects neural signature of memory integration during learning and the causal role of microglia in this process. This research will result in a paradigm shift to use noninvasive brain stimulation prophylactically in people at risk of AD prior to plaques or symptoms. Furthermore, this research will reveal new mechanisms by which flicker stimulation promotes protective immune function and promotes memory.

γ感觉闪烁对阿尔茨海默病早期干预的机制及保护作用 影响 阿尔茨海默病（AD）需要一种新的治疗方法来干预之前或早期的疾病。在 在上一个资助期，PI和团队发现伽马，或40赫兹，感官闪烁（光和声音 以毫秒级的精度打开和关闭）在阿尔茨海默病病理学的小鼠模型中具有有益的效果， 症状分期伽马闪烁驱动伽马神经活动，减少淀粉样斑块，招募小胶质细胞 吞噬淀粉样蛋白β（Aβ），并恢复Aβ病理小鼠的记忆行为。这项建议标志着 这项研究的令人兴奋的转变是在斑块积累之前的临床前阶段干预AD， 开始出现记忆缺陷小胶质细胞和细胞因子在AD中发挥疾病修饰作用并影响网络 功能，具有潜在的破坏性或有益的影响。我们团队和其他人最近的研究表明， 保护性免疫基因和蛋白质签名在早期AD发病机制中的作用。本提案的目的是 确定闪烁刺激如何影响临床前AD阶段的保护性免疫功能， 记忆的特征，并阐明这些影响的机制。使用最先进的转录组学和 通过蛋白质组学分析和大规模神经记录，我们将确定闪烁对小胶质细胞的影响 记忆的表型和神经特征使用药理学和遗传学操作，我们将 确定小胶质细胞和小胶质细胞信号在介导闪烁对小胶质细胞的影响中的因果作用 表型和网络功能。我们将确定闪烁诱导的小胶质细胞基因转录是否与 最近定义了存在于早期AD中的人类抗炎性小胶质细胞标志物， 从人体组织的尖端细胞类型特异性分析。目标1将定义闪烁对小胶质细胞的影响 临床前阶段的表型，涉及的分子机制，以及人类相关的转录 方面的影响.目标2将建立临床前闪烁如何影响学习过程中记忆整合的神经信号 以及小胶质细胞在这一过程中的因果作用。这项研究将导致一个范式的转变，使用非侵入性 在斑块或症状出现之前，脑刺激对有AD风险的人有治疗作用。此外，本研究 将揭示闪烁刺激促进保护性免疫功能的新机制， 记忆