Noninvasive Neurostimulation to Reduce Pathology in a Female Mouse Model of Alzheimer's Disease

超过50万美国退伍军人患有阿尔茨海默病（AD）。随着AD诊断的增加， 这一年，急需治疗。尽管有这种需要，但对于AD并不存在明确有效的治疗， 在非人类模型中测试的干预措施往往不能转化为成功的临床试验。因为女性更 与男性相比，男性更容易患AD，因此在评估AD治疗时，必须将性别作为决定因素 临床使用前的治疗。优化的治疗有可能逆转AD神经病理学， 需要在神经变性和细胞死亡之前的前驱期减轻认知损害。 暴露于40 Hz的无创视听神经刺激（伽马闪烁）刺激神经活动 在首先受到AD病理影响的大脑区域中，这些区域对学习和记忆很重要，包括 海马（HPC）和前额叶皮质（PFC）。伽玛闪烁招募小胶质细胞，主要的免疫细胞， 在淀粉样变性的雄性5XFAD小鼠模型中， WT雄性小鼠中的表达。像多巴胺和去甲肾上腺素这样的神经递质调节激活， 增殖和从免疫细胞释放细胞因子。此外，AD病理学包括以下表达的破坏： 脑源性神经营养因子（BDNF）是学习记忆的重要营养因子。这些 随着AD的进展，神经调节剂减少，揭示了治疗神经调节剂的潜在治疗靶点。 功能障碍和疾病。尽管已知AD病理学存在性别差异，但在如何实现AD病理学方面存在知识差距。 闪烁非侵入性地激发女性免疫反应、神经调质和认知的变化。 AD中侵袭性淀粉样蛋白积聚的雌性5XFAD小鼠模型的初步数据表明， 不同的频率可能是为每种性别最佳调整神经刺激的关键。因此， 这个提议是为了检验这样一个假设，即视听闪烁的特定频率对于改变 小胶质细胞的神经免疫反应和对学习和记忆重要的脑区域中的神经调质 受到神经退行性疾病的影响。通过CDA 2提出的研究， 将5XFAD小鼠暴露于慢性视听闪烁（1小时/天，持续7天），然后闪烁对1） 不同刺激频率的神经胶质反应谱，2）改变神经胶质的营养因子和神经递质 将测量反应性、认知和神经可塑性，以及3）工作记忆表现。 拟议的研究将在CDA 2的拟议5年时间轴内在中心进行， 亚特兰大VA的视觉和神经认知康复（CVNR）。可用的资源包括亚特兰大 埃默里大学Goizueta阿尔茨海默病研究中心，生物医学系 工程在格鲁吉亚技术，和埃默里的蛋白质组学和显微镜核心。指导团队和 CVNR将支持研究技术，实验室管理和赠款写作方面的培训， 有一个强大的基础，以实现她的目标，独立通过提交VA优异奖。 通过她在埃默里大学和格鲁吉亚理工学院的独特培训，结合通过 在CDA 2中，Prichard博士最终将作为终身教授从事研究和指导工作， VA研究员在她未来的比较认知和神经病理学实验室。她将利用啮齿动物模型 评估闪烁对AD病理学的影响，并将其应用于宠物犬与犬的非侵入性研究 认知功能障碍，一种自然发生的类人AD病理形式。职业道路的第一步是 在亚特兰大退伍军人管理局训练，以确定闪烁对免疫反应和神经调节剂的影响， 明确指出性别是疾病病因的重要因素， 动物模型和最终的临床试验。在完成奖学金后，她将学到宝贵的 在细胞形态学、神经免疫反应和蛋白质分析方面的研究技术， 在老龄化研究和疾病病理学的背景，并建立了一个网络的VA导师和合作者。

Over half a million U.S. veterans have Alzheimer’s disease (AD). With AD diagnoses increasing each year, treatments are urgently needed. Despite this need, no clear effective treatment exists for AD and interventions tested in nonhuman models often fail to translate to successful clinical trials. As women are more likely to develop AD than men, AD treatments must address sex as determining factor when evaluating treatments prior to clinical use. Optimized treatments that have the potential to reverse AD neuropathology and mitigate cognitive impairment at prodromal stages, prior to neural degeneration and cell death, are required. Exposure to noninvasive audiovisual neurostimulation at 40Hz (gamma flicker) stimulates neural activity in brain regions first affected by AD pathology that are important for learning and memory, including the hippocampus (HPC) and prefrontal cortex (PFC). Gamma flicker recruits microglia, the primary immune cell of the brain, in the HPC and visual cortex in male 5XFAD mouse models of amyloidosis, as well as cytokine expression in WT male mice. Neurotransmitters like dopamine and norepinephrine modulate the activation, proliferation, and cytokine release from immune cells. Further, AD pathology includes disrupted expression of brain-derived neurotrophic factor (BDNF), an important trophic factor for learning and memory. These neuromodulators are reduced as AD progresses, revealing potential therapeutic targets for treating neural dysfunction and disease. Despite known sex differences in AD pathology, there is a knowledge gap on how flicker noninvasively elicits changes in the immune response, neuromodulators, and cognition in females. Preliminary data in female 5XFAD mouse models of aggressive amyloid accumulation in AD suggest that different frequencies could be key to optimally tuning neurostimulation for each sex. Thus, the central goal of this proposal is to test the hypothesis that specific frequencies of audiovisual flicker are optimal for altering the neuroimmune response of microglia and neuromodulators in brain regions important for learning and memory affected by neurodegenerative disease for each sex. Through the CDA2 proposed research, male and female 5XFAD mice will be exposed to chronic audiovisual flicker (1hr/ day for 7 days), then flicker’s effects on 1) the spectrum of glia reactivity across stimulation frequencies, 2) trophic factors and neurotransmitters that alter glia reactivity, cognition, and neuroplasticity, and 3) working memory performance, will be measured. The proposed research will take place over the proposed 5-year timeline of the CDA2 at the Center for Visual and Neurocognitive Rehabilitation (CVNR) of the Atlanta VA. The resources available include the Atlanta CVNR, Emory University’s Goizueta Alzheimer’s Disease Research Center, the Department of Biomedical Engineering at Georgia Tech, and Emory’s Proteomics and Microscopy cores. The mentoring team and the CVNR will support training in research techniques, lab management, and grant writing to provide Dr. Prichard with a strong foundation to achieve her goals of independence through the submission of a VA Merit Award. Through her unique training at Emory University and Georgia Tech, combined with the training through the CDA2, Dr. Prichard will ultimately pursue a career in research and mentoring as a tenure-track professor and VA researcher in her future comparative cognition and neuropathology lab. She will utilize rodent models for assessment of flicker’s effects on AD pathology and apply this to noninvasive studies of pet dogs with canine cognitive dysfunction, a naturally occurring form of human-like AD pathology. The first step in this career path is to train at the Atlanta VA to establish the effects of flicker on the immune response and neuromodulators, explicitly addressing sex as an important factor in disease etiology, progressing toward treatment in higher-order animal models and ultimately clinical trials. Upon completion of the fellowship, she will have learned valuable research techniques in cell morphology, neuroimmune responses, and protein analyses, developed a strong background in aging research and disease pathology, and built a network of VA mentors and collaborators.