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

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.

摘要