Therapeutic Potential of FGF21 for Alzheimer’s Disease

FGF21 对阿尔茨海默病的治疗潜力

基本信息

批准号：
10740063
负责人：
Matthew Joseph Potthoff
金额：
$ 59.07万
依托单位：
UNIVERSITY OF IOWA
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：
2023-07-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740063
关键词：
3xTg-AD mouse Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Animal Model Attenuated Back Body Weight decreased Brain Brain Diseases Brain region Cells Central Nervous System Clinical Trials Cognition Cognitive aging Cytoprotection Data Defect Dementia Diabetes Mellitus Disease Disease Progression Dissection Endocrine FGFR1 gene Fatty acid glycerol esters Fibroblast Growth Factor Receptors GLUT 4 protein Genes Genetic Glycoproteins Hippocampus Homeostasis Hormones Human Impaired cognition Impairment In Vitro Insulin Knock-out Knowledge Learning Life Expectancy Liver Long-Term Potentiation Mediating Memory Memory impairment Metabolic Metabolic Diseases Metabolic Pathway Metabolic dysfunction Metabolism Mitochondria Modeling Mus Nerve Degeneration Neurodegenerative Disorders Neuronal Plasticity Neurons Obesity Oxidative Stress Pathologic Pathway interactions Peripheral Physiological Physiological Processes Physiology Play Publishing Rodent Role Signal Transduction Slice Specificity Stress Symptoms Techniques Thalamic structure Therapeutic Tissues Up-Regulation Vertebral column Wild Type Mouse Work abeta accumulation blood glucose regulation cholinergic neuron cognitive function comorbidity effective therapy fibroblast growth factor 21 glucose metabolism hyperphosphorylated tau improved in vivo innovation insulin sensitivity insulin signaling metabolic profile metabolomics mimetics mitochondrial dysfunction mouse model neuronal metabolism neuroprotection neurotransmission nonhuman primate novel novel strategies pharmacologic prevent receptor reduce symptoms response spatial memory symptomatic improvement way finding

项目摘要

Project Summary / Abstract Cognitive dysfunction and dementia rates are increasing worldwide in part due to the significant increase in life expectancy. Alzheimer’s disease (AD), the main cause of dementia, is a progressive neurodegenerative brain disease characterized by impairments in cognitive function. Aging is the main risk factor for AD and unfortunately there is no effective treatment for slowing down aging or treating AD. Current approaches to treat AD (e.g., amyloid beta accumulation and tau hyperphosphorylation) have been unsuccessful which calls for novel approaches to treat the full spectrum of this disease. Recent studies have postulated that cognitive decline and AD might be manifestations of metabolic disorders. In particular, changes in glucose metabolism and brain insulin sensitivity have been identified as common features observed in AD. Our published works reveal that the endocrine hormone fibroblast growth factor 21 (FGF21) decreases body weight during obesity, improves insulin sensitivity, and corrects metabolic dysfunctions in animal models. Clinical trials with FGF21 mimetics have also demonstrated the efficacy of targeting this pathway to improve metabolic profiles in humans. Interestingly, recent data suggests that FGF21 administration may also prevent neurodegeneration and pathological deficits in animal models of AD. While circulating FGF21 levels are derived primarily by the liver, our recently published study reveals the unexpected discovery that FGF21 is also expressed in a very specific region of the central nervous system. Specifically, FGF21 is expressed in the retrosplenial cortex and can signal to the hippocampus and can regulate learning and memory. A previous study demonstrates that FGF21 is induced from neurons in response to mitochondrial stress. These observations are the backbone of our main hypothesis in this proposal which seeks to interrogate whether FGF21 signals to neurons in hippocampus to not only improve neuronal metabolism and memory, but also improves AD symptoms. This proposal employs various genetic AD mouse models to explore different aspects of AD, as well as genetic and pharmacological approaches, to investigate the effects of FGF21 and in the improvement of memory and cognition. Together, these studies will not only further our knowledge of the role of FGF21 in neuronal metabolism but will also provide a better understanding of potential metabolic abnormalities during AD. Finally, these studies may reveal a potential therapeutic approach to treat AD and its related dementias.

项目概要/摘要世界范围内认知功能障碍和痴呆症的发病率正在增加，部分原因是认知功能障碍和痴呆症的发病率显着增加阿尔茨海默病（AD）是痴呆症的主要原因，是一种进行性的疾病。以认知功能受损为特征的神经退行性脑部疾病是主要风险。不幸的是，没有有效的治疗方法可以减缓衰老或治疗 AD。目前治疗 AD 的方法（例如，β 淀粉样蛋白积累和 tau 蛋白过度磷酸化）已被不成功，这需要新的方法来治疗这种疾病的全部谱最近的研究。假设认知能力下降和 AD 可能是代谢紊乱的表现。葡萄糖代谢和大脑胰岛素敏感性的变化已被确定为共同特征我们发表的研究成果揭示了内分泌激素成纤维细胞生长因子 21。 (FGF21) 降低肥胖期间的体重，提高胰岛素敏感性，并纠正代谢 FGF21 模拟物的临床试验也证明了其功效。针对这一途径来改善人类的代谢状况。 FGF21 给药还可以预防动物模型中的神经变性和病理缺陷 AD。虽然循环中的 FGF21 水平主要来自肝脏，但我们最近发表的研究表明意外发现 FGF21 也在中枢神经系统的一个非常特定的区域表达具体来说，FGF21 在压后皮质中表达，可以向海马体发出信号。先前的研究表明，FGF21 是由 FGF21 诱导的。这些观察结果是我们主要假设的支柱。该提案旨在询问 FGF21 向海马神经元发出的信号是否不仅改善神经代谢和记忆力，还能改善 AD 症状。各种遗传 AD 小鼠模型，以探索 AD 的不同方面，以及遗传和药理学方法，研究 FGF21 的作用以及改善记忆力和总之，这些研究不仅将进一步加深我们对 FGF21 在神经元中作用的了解。代谢，而且还可以更好地了解 AD 期间潜在的代谢异常。最后，这些研究可能揭示治疗 AD 及其相关痴呆症的潜在治疗方法。