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 50 万美国退伍军人患有阿尔茨海默病 (AD)，而且 AD 诊断数量逐年增加。尽管有这种需求，但目前还没有针对 AD 和 AD 的明确有效的治疗方法。由于女性较多，对经过测试的非人类模型的干预往往无法转化为成功的临床试验。比男性更容易患 AD，AD 治疗在评估时必须将性别作为决定因素临床使用前的优化治疗有可能逆转 AD 神经病理学和需要在神经变性和细胞死亡之前的前驱阶段出现认知障碍。暴露于 40Hz（伽马闪烁）的无创视听神经刺激会刺激神经活动首先受 AD 病理影响的大脑区域对学习和记忆很重要，包括海马体 (HPC) 和前额皮质 (PFC) 会招募小胶质细胞，这是大脑的主要免疫细胞。雄性淀粉样变性 5XFAD 小鼠模型的大脑、HPC 和视觉皮层以及细胞因子 WT雄性小鼠中的神经递质如多巴胺和去甲肾上腺素的表达调节激活，此外，AD 病理学还包括免疫细胞的增殖和细胞因子的表达破坏。脑源性神经营养因子（BDNF），是学习和记忆的重要营养因子。随着 AD 的进展，神经调节剂会减少，揭示了治疗神经元的潜在治疗靶点尽管 AD 病理学存在性别差异，但对于如何进行治疗仍存在知识差距。闪烁非侵入性地引起女性免疫反应、神经调节剂和认知的变化。 AD 中侵袭性淀粉样蛋白积累的雌性 5XFAD 小鼠模型的初步数据表明不同的频率可能是优化调整每个性别神经刺激的关键。该提案是为了测试以下假设：视听闪烁的特定频率对于改变视听闪烁是最佳的。对学习和记忆很重要的大脑区域小胶质细胞和神经调节剂的神经免疫反应通过 CDA2 提出的研究，男性和女性都受到神经退行性疾病的影响。 5XFAD 小鼠将暴露于慢性视听闪烁（1 小时/天，持续 7 天），然后闪烁对 1) 的影响神经胶质细胞在刺激频率下的反应谱，2) 改变神经胶质细胞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 CDA2 中心的拟议 5 年时间内进行亚特兰大 VA 的视觉和神经认知康复 (CVNR) 可用资源包括亚特兰大。 CVNR，埃默里大学戈伊苏埃塔阿尔茨海默病研究中心，生物医学系佐治亚理工学院的工程，以及埃默里大学的蛋白质组学和显微镜学核心。 CVNR 将支持研究技术、实验室管理和资助写作方面的培训，为 Prichard 博士提供帮助通过提交 VA 优异奖，为实现独立目标奠定了坚实的基础。通过她在埃默里大学和佐治亚理工学院的独特培训，结合通过通过 CDA2，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中，她将利用啮齿动物模型进行研究。评估闪烁对 AD 病理学的影响，并将其应用于宠物狗与犬的无创研究认知功能障碍，一种类似人类 AD 病理学的自然形式。这一职业道路的第一步是。在亚特兰大退伍军人管理局进行培训，以确定闪烁对免疫反应和神经调节剂的影响，明确将性别视为疾病病因学的一个重要因素，并朝着更高阶的治疗方向发展完成研究金后，她将在动物模型和最终的临床试验中学到宝贵的知识。细胞形态、神经免疫反应和蛋白质分析方面的研究技术，开发了强大的具有衰老研究和疾病病理学背景，并建立了 VA 导师和合作者网络。