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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）。随着AD诊断的增加