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

摘要 衰老是包括神经退行性疾病在内的大多数慢性疾病的主要风险因素。 现在有充分的证据表明，在老鼠身上，衰老的过程可以通过 靶向许多细胞和分子途径的药理学化合物， 参与衰老过程，也延缓多种形式的晚年疾病，包括 阿尔茨海默病（AD）。与干预测试计划（ITP）合作，我们 最近证明，FDA批准的抗糖尿病药物Canagliflozin（Cana），一种钠- 葡萄糖转运蛋白2（SGLT 2）抑制剂，延长了遗传多样性UM-HET 3的寿命 雄性小鼠减少14%，对雌性小鼠没有影响。问题是卡纳是否有益于 对大脑老化的影响或改善大脑中与年龄相关的疾病仍然是开放的。 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的区域特异性神经炎症。此外，Cana 治疗改善了老年雄性小鼠的自发活动和探索行为。我们的初步 数据进一步揭示了下丘脑转录组的显著变化， 与炎症反应激活相关的基因的表达，特别是与 老年Cana治疗小鼠中的NLRP 3炎性小体活化。我们的中心假设是卡纳 显示出可用于治疗老化脑的神经保护特性 和/或神经变性疾病。这一假设将使用遗传多样性进行评估。 UM-HET 3小鼠从7月龄开始用Cana喂养，然后纵向地组合 生理学、分子学和遗传学方法。我们将确定卡纳治疗的效果 对衰老过程中认知功能的影响，并将其与老年人中Cana水平的测量相关联。 个脑袋我们将评估Cana对小胶质细胞炎性小体激活的影响，并研究脑空间 转录组学变化，以确定介导衰老的关键途径/基因。 Cana的药理作用最后，我们将确定Cana对认知功能的影响。 使用两种良好建立的AD、5xFAD和PS19 Tau小鼠模型，我们的研究 测试已确定药物对认知退化的药理作用的潜力 在衰老，以及确定新的细胞和分子机制， 药理作用。综上所述，我们的研究将验证Cana作为一种药物， 用于预防或治疗人类AD。

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.