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病的主要危险因素。 现在有充分的证据表明，在老鼠身上，衰老的过程可以通过 以许多细胞和分子通路为靶点的药理化合物 与衰老过程有关，还延缓了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，我们有 最近证明，FDA批准的抗糖尿病药物Canagliflzin(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 雄鼠减少14%，对雌鼠没有影响。CANA是否有益的问题 对大脑老化或改善大脑中与年龄相关的疾病的影响仍然悬而未决。 我们的新研究表明，CANA显示出神经保护特性，如改善 中枢胰岛素反应性和减少区域特异性神经炎。此外，CANA 治疗改善了老年雄性小鼠的运动活动和探索行为。我们的预赛 数据进一步显示，下丘脑转录组的显著变化与 炎症反应激活相关基因的表达 CANA处理的老年小鼠的NLRP3炎症体激活。我们的中心假设是CANA 显示出可能适用于治疗脑老化的神经保护特性 和/或神经退行性疾病。这一假设将通过基因多样性进行评估。 UM-HET3小鼠从7个月龄开始喂食CanA，并通过联合 生理、分子和遗传方法。我们将确定CANA治疗的效果 在衰老过程中的认知功能，并将其与老年患者CANA水平的测量相关联 大脑。我们将评估CANA对小胶质细胞炎性小体激活的影响，并研究大脑空间 老年小鼠转录水平的变化以确定关键的途径/基因 CANA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PS19Tau。我们的研究已经 测试一种已确定的药物对认知退化的药理作用的可能性 以及确定导致衰老的新的细胞和分子机制 药理作用。综上所述，我们的研究将证实Cana是一种可以迅速 用于预防或治疗人类的阿尔茨海默病。

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.