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.

项目摘要 /摘要认知功能障碍和痴呆率率在全球范围内增加，部分原因是在预期寿命中。阿尔茨海默氏病（AD）是痴呆的主要原因，是一种进步神经退行性脑疾病的特征是认知功能受损。衰老是主要风险 AD的因素，不幸的是，没有有效的治疗方法可以减慢衰老或治疗AD。当前治疗AD的方法（例如，淀粉样蛋白β积累和Tau高磷酸化）已是未能成功地采用新颖的方法来治疗这种疾病的全部疾病。最近的研究已经发布了认知能力下降和AD可能是代谢障碍的表现。尤其，葡萄糖代谢和脑胰岛素敏感性的变化已被确定为常见特征在AD中观察到。我们发表的作品表明，内分泌果烯成纤维细胞生长因子21 （FGF21）减轻肥胖期间体重，提高胰岛素敏感性并纠正代谢动物模型中的功能障碍。 FGF21 Mimetics的临床试验也证明了针对这种改善人类代谢谱的途径。有趣的是，最近的数据表明 FGF21给药还可以防止在动物模型中的神经退行性和病理缺陷广告。虽然循环FGF21水平主要由肝脏得出，但我们最近发表的研究揭示了意外的发现，即FGF21也在中枢神经的非常特定的区域中表达系统。特别是，FGF21在后泛胞皮层中表达，可以发信号并可以调节学习和记忆。先前的研究表明，FGF21是从神经元响应线粒体应激。这些观察是我们主要假设的骨干在此提案中，试图询问FGF21是否向海马的神经元发出信号改善神经元的代谢和记忆力，但也可以改善AD症状。该提案员工各种遗传AD小鼠模型，以探索AD的不同方面，以及遗传和药理方法，研究FGF21的影响以及改善记忆和认识。这些研究不仅将进一步了解FGF21在神经元中的作用代谢，但还将为AD期间的潜在代谢异常提供更好的理解。最后，这些研究可能揭示了治疗AD及其相关痴呆症的潜在治疗方法。