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:
- 金额:--
- 依托单位:
- 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:
- 关键词:AddressAffectAgingAlzheimer like pathologyAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmericanAmyloidAmyloid beta-ProteinAmyloidosisAnimal ModelAwardBiomedical EngineeringBlood - brain barrier anatomyBrain regionBrain-Derived Neurotrophic FactorCanis familiarisCareer ChoiceCell DeathCellsCellular MorphologyCentral Nervous SystemChronicClinicalClinical TrialsCognitionCognitive deficitsDataDiseaseDisease ProgressionDisease modelDopamineDrug TargetingEtiologyExposure toFellowshipFemaleFoundationsFrequenciesFunctional disorderFutureGoalsGrantHigh Pressure Liquid ChromatographyHippocampusHourHumanImmuneImmune responseImpaired cognitionInflammationInterventionInvestigationKnowledgeLearningMeasuresMemoryMemory impairmentMentorsMethodsMicrogliaMicroscopyModelingMorphologyMusNerve DegenerationNeurocognitiveNeurodegenerative DisordersNeurogliaNeuroimmuneNeuromodulatorNeuronal DysfunctionNeuronal PlasticityNeuronsNeurotransmittersNorepinephrinePathologyPerformancePhenotypePrefrontal CortexProliferatingProtein AnalysisProteomicsRadialRehabilitation therapyResearchResearch PersonnelResearch TechnicsResourcesRiskRisk FactorsRodent ModelSenile PlaquesSensory ProcessSex DifferencesShort-Term MemoryStressStructureTestingTimeTrainingTraining SupportTranslatingTraumaUniversitiesVeteransVisualVisual CortexWild Type MouseWomanWritingarmbrain cellcareercomparativecytokineeffective interventioneffective therapyimmune activationimprovedmalemenmilitary servicemouse modelneural stimulationneuroinflammationneuron lossneuropathologyneuroregulationnovelpersonalized medicinepotential biomarkerpreventprofessorrecruitresponsesexspatial memorytenure tracktherapeutic targettimelinetreatment optimizationwater 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
项目成果
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