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

伽玛感觉闪烁作为阿尔茨海默病的早期干预：机制和保护 效应 阿尔茨海默病(AD)需要一种新的治疗方法来在疾病之前或早期进行干预。在……里面 在上一个资助期，PI和团队发现伽马，或40赫兹，感觉闪烁(光和声音 以毫秒级的精度打开和关闭)在阿尔茨海默病小鼠模型中具有有益的效果 有症状的阶段。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β蛋白(Aβ)，并恢复Aβ病理小鼠的记忆行为。这项提议标志着 这项研究的令人兴奋的转变是在斑块聚集之前的临床前阶段干预AD和 记忆缺陷的开始。小胶质细胞和细胞因子在AD中起疾病修饰作用并影响网络 功能，具有潜在的损害或有益的影响。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信号在早期AD发病机制中的作用。这项提议的目标是 确定闪烁刺激如何影响临床前AD阶段的保护性免疫功能以改善神经 记忆的特征，并阐明这些影响的机制。使用尖端的转录和 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。利用药理学和遗传操作，我们将 确定小胶质细胞和小胶质细胞信号在闪光对小胶质细胞影响中的因果作用 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 利用我们团队的发现，最近确定了AD早期存在的人类抗炎小胶质细胞标记物 来自对人体组织的尖端细胞类型的特定分析。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、涉及的分子机制和与人类相关的转录 效果。目标2将确定临床前闪烁如何影响学习过程中记忆整合的神经特征 以及小胶质细胞在这一过程中的因果作用。这项研究将导致范式的转变，使用非侵入性 对阿尔茨海默病高危人群预防性脑刺激先于斑块或症状。此外，这项研究还 将揭示闪光刺激促进保护性免疫功能和促进 记忆。

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.