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

无创神经刺激可减少阿尔茨海默病雌性小鼠模型的病理学变化

基本信息

批准号：
10640335
负责人：
Ashley Prichard
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640335
关键词：
Address Affect Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer’s disease biomarker American Amyloid Amyloid beta-Protein Amyloidosis Animal Model Award Biomedical Engineering Blood - brain barrier anatomy Brain region Brain-Derived Neurotrophic Factor Canis familiaris Career Choice Cell Death Cells Cellular Morphology Central Nervous System Chronic Clinical Clinical Trials Cognition Cognitive deficits Data Disease Disease Progression Disease model Dopamine Drug Targeting Etiology Exposure to Fellowship Female Foundations Frequencies Functional disorder Future Goals Grant High Pressure Liquid Chromatography Hippocampus Hour Human Immune Immune response Impaired cognition Inflammation Intervention Investigation Knowledge Learning Measures Memory Memory impairment Mentors Methods Microglia Microscopy Modeling Morphology Mus Nerve Degeneration Neurocognitive Neurodegenerative Disorders Neuroglia Neuroimmune Neuromodulator Neuronal Dysfunction Neuronal Plasticity Neurons Neurotransmitters Norepinephrine Pathology Performance Phenotype Prefrontal Cortex Proliferating Protein Analysis Proteomics Radial Rehabilitation therapy Research Research Personnel Research Technics Resources Risk Risk Factors Rodent Model Senile Plaques Sensory Process Sex Differences Short-Term Memory Stress Structure Testing Time Training Training Support Translating Trauma Universities Veterans Visual Visual Cortex Wild Type Mouse Woman Writing arm brain cell career comparative cytokine effective intervention effective therapy immune activation improved male men military service mouse model neural stimulation neuroinflammation neuron loss neuropathology neuroregulation novel personalized medicine potential biomarker prevent professor recruit response sex spatial memory tenure track therapeutic target timeline treatment optimization water maze

项目摘要

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.

超过一百万的美国退伍军人患有阿尔茨海默氏病（AD）。随着广告诊断的增加一年，迫切需要治疗。尽管需要此需求，但对于AD和在非人类模型中测试的干预措施通常无法转化为成功的临床试验。随着女性更多广告处理可能比男性发展广告，在评估时必须将性作为决定因素临床使用之前的治疗。优化的治疗方法有可能逆转AD神经病理学和在神经退行性和细胞死亡之前，在前驱阶段的认知障碍是缓解认知障碍。在40Hz（伽马闪烁）处暴露于无创的视听神经刺激会刺激神经活动在大脑区域中，首先受到广告病理影响，对学习和记忆很重要，包括海马（HPC）和前额叶皮层（PFC）。伽玛闪烁招募小胶质细胞，这是主要的免疫细胞雄性5xFAD小鼠淀粉样变性的HPC和视觉皮层中的大脑以及细胞因子 WT雄性小鼠的表达。多巴胺和去甲肾上腺素等神经递质调节激活，增殖和细胞因子从免疫细胞释放。此外，AD病理包括中断的表达脑衍生的神经营养因子（BDNF），这是学习和记忆的重要营养因素。这些随着AD的进行，神经调节剂减少了，揭示了治疗神经的潜在治疗靶标功能障碍和疾病。尽管广告病理学上的性别差异已知，但关于如何闪烁的无创性会导致女性的免疫反应，神经调节剂和认知变化。雌性5xFAD小鼠在AD中积累的淀粉样蛋白积累模型的初步数据表明不同的频率可能是每种性别最佳调整神经刺激的关键。那，是该建议是测试以下假设：视听闪烁的特定频率是更改的最佳选择。大脑区域中小胶质细胞和神经调节剂的神经免疫反应对于学习和记忆很重要每种性别都受神经退行性疾病的影响。通过CDA2提出的研究，男性和女性 5XFAD小鼠将暴露于慢性视听闪烁（每天1小时7天），然后闪烁对1）跨刺激频率的胶质反应性光谱，2）营养因子和神经递质改变神经胶质将测量反应性，认知和神经可塑性以及3）工作记忆表现。拟议的研究将在拟议的5年CDA2时间表上进行弗吉尼亚州亚特兰大的视觉和神经认知康复（CVNR）。可用的资源包括亚特兰大 CVNR，埃默里大学的Goizueta阿尔茨海默氏病研究中心，生物医学系佐治亚理工学院的工程以及埃默里的蛋白质组学和显微镜核心。心理团队和 CVNR将支持研究技术，实验室管理和赠款写作的培训，以提供Prichard博士通过提交VA功绩奖，以实现她的独立目标的坚实基础。通过她在埃默里大学和佐治亚理工学院的独特培训，结合了通过 CDA2，Prichard博士最终将从事研究和心理职业，担任终身教授和 VA研究人员在她未来的比较认知和神经病理学实验室中。她将利用啮齿动物模型评估Flicker对AD病理学的影响，并将其应用于犬类宠物犬的无创研究认知功能障碍，一种天然发生的人类AD病理学形式。这条职业道路的第一步是在弗吉尼亚州亚特兰大训练以建立闪烁对免疫反应和神经调节剂的影响，明确将性作为疾病病因的重要因素，朝着高阶的治疗迈进动物模型，最终进行临床试验。研究金完成后，她将学到宝贵的细胞形态，神经免疫反应和蛋白质分析的研究技术发展了衰老研究和疾病病理学的背景，并建立了VA导师和合作者网络。