Sex-based differences of a high fat diet in Alzheimer's disease (AD): Can nilotinib reverse bioenergetic and neuropathological deficits?

阿尔茨海默病 (AD) 中高脂肪饮食的性别差异：尼罗替尼能否逆转生物能量和神经病理学缺陷？

• 批准号: 10629882
• 负责人: BENEDICT C ALBENSI
• 金额: $ 15.4万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629882
• 关键词: 3xTg-AD mouse; AD transgenic mice; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Amyloid beta-Protein; Animal Model; Appearance; Astrocytes; Attenuated; Behavioral; Bioenergetics; Biological Markers; Clinical Trials; Cognition; Cognitive; Cultured Cells; Data; Dementia; Disease; Disparity; Exhibits; FDA approved; Female; Functional disorder; Genus Hippocampus; Goals; Heart; High Fat Diet; Impaired cognition; Individual; Inflammation; Inflammatory; Knowledge; Link; Medical; Memory; Metabolic; Metabolic Diseases; Metabolism; Methods; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; OPA1 gene; Obesity; Outcome; Oxidative Stress; Oxygen Consumption; Pathology; Patients; Pharmaceutical Preparations; Prediabetes syndrome; Process; Publications; Rodent Model; Sex Bias; Sex Differences; Testing; Treatment outcome; Unhealthy Diet; Woman; Work; cerebrovascular health; chemotherapeutic agent; clinically relevant; cognitive enhancement; cognitive function; comorbidity; improved; improved outcome; in vivo; insight; leukemia; male; men; mitochondrial dysfunction; morris water maze; mouse model; neuropathology; novel; object recognition; patient population; phase 2 study; phase III trial; protein expression; sex; tau Proteins; white matter; 3xTg-AD mouse; AD transgenic mice; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Amyloid beta-Protein; Animal Model; Appearance; Astrocytes; Attenuated; Behavioral; Bioenergetics; Biological Markers; Clinical Trials; Cognition; Cognitive; Cultured Cells; Data; Dementia; Disease; Disparity; Exhibits; FDA approved; Female; Functional disorder; Genus Hippocampus; Goals; Heart; High Fat Diet; Impaired cognition; Individual; Inflammation; Inflammatory; Knowledge; Link; Medical; Memory; Metabolic; Metabolic Diseases; Metabolism; Methods; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; OPA1 gene; Obesity; Outcome; Oxidative Stress; Oxygen Consumption; Pathology; Patients; Pharmaceutical Preparations; Prediabetes syndrome; Process; Publications; Rodent Model; Sex Bias; Sex Differences; Testing; Treatment outcome; Unhealthy Diet; Woman; Work; cerebrovascular health; chemotherapeutic agent; clinically relevant; cognitive enhancement; cognitive function; comorbidity; improved; improved outcome; in vivo; insight; leukemia; male; men; mitochondrial dysfunction; morris water maze; mouse model; neuropathology; novel; object recognition; patient population; phase 2 study; phase III trial; protein expression; sex; tau Proteins; white matter

ABSTRACT Metabolic disorders (i.e. obesity, prediabetes or type 2 diabetes), often resulting from poor diet, is a significant risk factor for Alzheimer’s disease (AD). Several common neurodegenerative mechanisms in these two conditions have been identified, including oxidative stress, mitochondrial dysfunction, and inflammation. Changes in metabolism and mitochondrial bioenergetics may be at the heart of both metabolic disorders and AD but may be affecting men and women differently. Although AD treatments exist, none are very effective, and certainly no drugs are sex-specific, creating a significant unmet medical need. Interestingly, several clinical trials testing nilotinib, a repurposed leukemia drug, have shown promise for use in treating AD and other neurodegenerative diseases. In addition to attenuating hallmark pathology, we recently demonstrated that nilotinib improves mitochondrial function and bioenergetics in cultured cells from the 3xTg-AD mouse model for AD. In this study, our specific objective is to use a high fat diet (HFD) to model metabolic disease in 3xTg-AD mice and evaluate sex-differences associated with bioenergetic, cognitive, and neuropathological outcomes, as well as whether nilotinib can improve them. The rationale for the proposed work is further supported by a recent phase II study conducted by our collaborator, Dr. Scott Turner, that showed 12 months of treatment with nilotinib, at 150 mg/day for 26 weeks followed by 300 mg/day for 26 weeks was safe, tolerable, and effective in patients with mild to moderate AD. Here, we hypothesize that nilotinib will improve mitochondrial bioenergetics, enhance cognitive function, and reduce biomarkers of AD pathology in a sex-dependent manner in 3xTg-AD mice subjected to a HFD. In Aim 1, we will determine whether in vivo treatment (100 or 250 mg/kg for 2 months) with nilotinib improves mitochondrial function and bioenergetics in 3xTg-AD mice in the absence and presence of HFD-induced metabolic disease. In Aim 2, we will investigate whether in vivo treatment with nilotinib can reverse cognitive-behavioral deficits in 3xTg-AD mice in the absence and presence of metabolic disease. Finally, in Aim 3, we will characterize the effects of in vivo treatment with nilotinib on AD-associated neuropathology in 3xTg-AD mice in the absence and presence of metabolic disease. The mechanisms by which nilotinib may improve outcomes in vivo, as well as patient populations for whom nilotinib treatment may be safe and effective (i.e., based on sex and comorbid metabolic disease, present in 80% of AD patients), have yet to be adequately explored in rodent models prior to the commencement of the drug’s phase III trial. We expect that a HFD will result in a wider range of bioenergetic, cognitive, and neuropathological consequences in female AD mice as compared to males. Overall, we expect nilotinib will improve mitochondrial function, ATP levels, AD-associated neuropathology, and cognition in 3xTg AD mice, including those subjected to a HFD.

抽象的 代谢性疾病（即肥胖，前糖尿病或2型糖尿病）通常是由于饮食不良而产生的，是一个重要的 阿尔茨海默氏病（AD）的危险因素。这两个中的几种常见的神经退行性机制 已经确定了条件，包括氧化应激，线粒体功能障碍和炎症。 新陈代谢和线粒体生物能学的变化可能是两种新陈代谢疾病的核心 广告但可能对男人和女人的影响有所不同。尽管存在广告疗法，但没有一个非常有效， 当然，没有药物是特定于性别的，因此产生了巨大的未满足的医疗需求。有趣的是，有几个临床 试验测试Nilotinib是一种重新利用的白血病药物，已显示出有望用于治疗AD和其他 神经退行性疾病。除了衰减Hallmark病理外，我们最近证明了 Nilotinib从3xTG-AD小鼠模型中改善培养细胞中的线粒体功能和生物能力 广告。在这项研究中，我们的具体目标是使用高脂肪饮食（HFD）在3XTG-AD中建模代谢疾病 小鼠并评估与生物能，认知和神经病理学结果相关的性别差异， 以及尼洛替尼是否可以改善它们。拟议工作的理由得到了 我们的合作者斯科特·特纳（Scott Turner）博士进行的第二阶段研究显示，该研究显示了12个月的治疗 尼洛替尼，以150 mg/天的150 mg/天，持续26周，然后以300 mg/天26周的26周安全，可容忍且有效 轻度至中度AD的患者。在这里，我们假设尼洛替尼将改善线粒体生物能学， 增强认知功能，并以3xtg-ad中的性别依赖性方式降低AD病理的生物标志物 接受HFD的小鼠。在AIM 1中，我们将确定体内治疗是否（1 100或250 mg/kg） 几个月）在不存在的情况下，尼洛替尼改善了3XTG-AD小鼠的线粒体功能和生物能力 HFD诱导的代谢疾病的存在。在AIM 2中，我们将调查体内治疗是否 尼洛替尼可以在不存在和存在代谢的情况下逆转3XTG-AD小鼠的认知行为定义 疾病。最后，在AIM 3中，我们将表征Nilotinib体内治疗对AD相关的影响 在不存在和存在代谢疾病的情况下，3XTG-AD小鼠的神经病理学。这些机制 哪种尼洛替尼可以改善体内的结局，以及尼洛替尼治疗的患者人群 安全有效（即基于性别和合并症的代谢疾病，有80％的AD患者）， 在该药物的III期试验开始之前，尚未在啮齿动物模型中充分探索。 我们希望HFD会导致更广泛的生物能力，认知和神经病理学 与男性相比，雌性AD小鼠的后果。总体而言，我们预计尼洛替尼将有所改善 线粒体功能，ATP水平，与AD相关的神经病理学和3XTG AD小鼠的认知，包括 受到HFD的人。