Canagliflozin as a Neuroprotective Agent to Improve Neuroinflammation and Cognitive Function during Aging

卡格列净作为神经保护剂改善衰老过程中的神经炎症和认知功能

基本信息

批准号：
10740151
负责人：
Marianna Sadagurski
金额：
$ 116.19万
依托单位：
WAYNE STATE UNIVERSITY
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：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740151
关键词：
Adult Affect Age Age Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Biochemical Brain Brain Diseases Brain region Cardiovascular Diseases Cells Chronic Disease Clinical Cognitive Collaborations Data Diabetes Mellitus Disease Disease Progression Dose Drug Prescriptions Elderly Exhibits Exploratory Behavior FDA approved Family Female Food Gene Expression Gene Expression Profile Genes Germ Cells Glucose Transporter Goals Hand Strength Health Heterogeneity High Pressure Liquid Chromatography Homeostasis Human Hypothalamic structure Immune In Vitro Inflammasome Inflammatory Inflammatory Response Insulin Intervention Lesion Lipids Long-Term Effects Longevity Measurement Measures Mediating Mediator Memory Metabolic Metabolic Control Metabolic Pathway Microglia Molecular Molecular Profiling Motor Activity Mus Neurodegenerative Disorders Neuroprotective Agents Non-Insulin-Dependent Diabetes Mellitus Outcome Pathology Pathway interactions Patients Pharmaceutical Preparations Physical activity Physiological Process Property Quality of life Risk Factors Senile Plaques Series Sex Differences Signal Pathway Signal Transduction Societies Sodium Testing Translating age related age related neurodegeneration aged aging brain attenuation brain cell cognitive function cognitive performance experimental study frailty genetic approach glucose metabolism improved in vivo inhibitor male marenostrin mouse model neuroinflammation neuroprotection novel novel therapeutics pharmacologic prevent programs response sex tau Proteins transcriptome transcriptomics translational impact

项目摘要

ABSTRACT Aging is the dominant risk factor for most chronic diseases including neurodegenerative diseases. There is now ample evidence, in mice, that the process of aging can be delayed by pharmacological compounds that target numerous cellular and molecular pathways that have been implicated in the aging process and also delay multiple forms of late-life illness, including Alzheimer's disease (AD). In collaboration with the Intervention Testing Program (ITP), we have recently demonstrated that an FDA-approved anti-diabetes drug, Canagliflozin (Cana), a sodium- glucose transporter 2 (SGLT2) inhibitor, extended the lifespan in the genetically diverse UM-HET3 male mice by 14%, without an effect on females. The question of whether Cana has beneficial effects on the aging brain or amelioration of age-associated diseases in the brain remains open. Our new study demonstrated that Cana exhibits neuroprotective properties, such as improved central insulin responsiveness and reduced region-specific neuroinflammation. Furthermore, Cana treatment improved locomotor activity and exploratory behavior in aged male mice. Our preliminary data further reveal significant changes in hypothalamic transcriptome associated with decreased expression of genes related to activation of inflammatory responses specifically genes related to NLRP3 inflammasome activation in aged Cana-treated mice. Our central hypothesis is that Cana exhibits neuroprotective properties that may be applicable for the treatment of the aging brain and/or neurodegenerative diseases. This hypothesis will be assessed using genetically diverse UM-HET3 mice fed with Cana from 7 months of age and followed longitudinally by combining physiological, molecular, and genetic approaches. We will determine the effects of Cana treatment on cognitive function during aging and correlate this with the measurements of Cana levels in the brain. We will assess the Cana effect on microglia inflammasome activation and study brain spatial transcriptomic changes in aged mice to identify key pathways/genes mediating the pharmacological effects of Cana. Finally, we will determine the effects of Cana on cognitive performance using two well-established mice models of AD, 5xFAD and PS19 Tau. Our study has the potential to test the pharmacological effects of an established drug on cognitive degeneration in aging, as well as to identify novel cellular and molecular mechanisms underlying this pharmacological effect. Taken together, our study will validate Cana as a drug that can be rapidly used for preventing or treating AD in humans.

抽象的衰老是大多数慢性疾病（包括神经退行性疾病）的主要危险因素。现在有充分的证据表明，在小鼠身上，可以通过以下方法延缓衰老过程：靶向多种细胞和分子途径的药理化合物与衰老过程有关，还可以延缓多种形式的晚年疾病，包括阿尔茨海默病（AD）。我们与干预测试计划 (ITP) 合作，最近证明 FDA 批准的抗糖尿病药物 Canagliflozin (Cana) 是一种钠- 葡萄糖转运蛋白 2 (SGLT2) 抑制剂，延长了遗传多样性 UM-HET3 的寿命雄性小鼠减少 14%，对雌性小鼠没有影响。迦拿是否有益的问题对衰老大脑的影响或改善大脑中与年龄相关的疾病的效果仍然存在。我们的新研究表明 Cana 具有神经保护特性，例如改善中枢胰岛素反应性和减少区域特异性神经炎症。此外，迦拿治疗改善了老年雄性小鼠的运动活动和探索行为。我们的初步数据进一步揭示了与减少相关的下丘脑转录组的显着变化与炎症反应激活相关的基因的表达，特别是与 Cana 治疗老年小鼠中 NLRP3 炎症小体的激活。我们的中心假设是迦拿具有神经保护特性，可用于治疗大脑老化和/或神经退行性疾病。该假设将使用遗传多样性进行评估 UM-HET3 小鼠从 7 个月大起开始用 Cana 喂养，并通过组合进行纵向跟踪生理学、分子和遗传学方法。我们将确定卡纳治疗的效果衰老期间的认知功能，并将其与 Cana 水平的测量结果相关联脑。我们将评估 Cana 对小胶质细胞炎症体激活的影响并研究大脑空间老年小鼠的转录组变化以确定介导的关键途径/基因卡纳的药理作用。最后，我们将确定 Cana 对认知的影响使用两种成熟的 AD 小鼠模型（5xFAD 和 PS19 Tau）来评估性能。我们的研究有测试现有药物对认知退化的药理作用的潜力以及确定其背后的新细胞和分子机制药理作用。总而言之，我们的研究将验证 Cana 是一种可以快速用于预防或治疗人类AD。