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:
  • 金额:
    $ 59.07万
  • 依托单位:
  • 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

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.
项目总结/摘要 认知功能障碍和痴呆症的发病率在全球范围内不断上升,部分原因是 在预期寿命上。阿尔茨海默病(AD)是痴呆症的主要原因,是一种进行性疾病, 以认知功能受损为特征的神经退化性脑疾病。老龄化是主要风险 AD的因素,不幸的是,没有有效的治疗方法来减缓衰老或治疗AD。 目前治疗AD的方法(例如,淀粉样蛋白β积累和tau过度磷酸化)已经被 这就需要新的方法来治疗这种疾病的全部谱。最近的研究 已经假设认知能力下降和AD可能是代谢紊乱的表现。特别是, 葡萄糖代谢和脑胰岛素敏感性的变化已被确定为共同特征 在AD中观察我们发表的工作表明,内分泌激素成纤维细胞生长因子21 (FGF 21)在肥胖期间降低体重,改善胰岛素敏感性,并纠正代谢 动物模型中的功能障碍。FGF 21模拟物的临床试验也证明了 靶向这一途径来改善人类的代谢状况。有趣的是,最近的数据表明, FGF 21给药还可以预防神经变性动物模型中的神经变性和病理缺陷。 AD.虽然循环中的FGF 21水平主要来自肝脏,但我们最近发表的研究表明, 出乎意料的发现是,FGF 21也在中枢神经系统的一个非常特定的区域表达, 系统具体地说,FGF 21在压后皮质中表达,并且可以向海马传递信号 并能调节学习和记忆。先前的研究表明,FGF 21是由 神经元对线粒体应激的反应。这些观察结果是我们主要假设的基础 在这个试图询问FGF 21是否向海马神经元发出信号的提议中, 改善神经元代谢和记忆,而且还改善AD症状。该提案采用 各种遗传性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FGF 21的作用和在改善记忆和 认知.总之,这些研究不仅将进一步加深我们对FGF 21在神经元细胞中作用的认识, 这将有助于更好地了解AD期间的潜在代谢异常。 最后,这些研究可能揭示一种潜在的治疗方法来治疗AD及其相关痴呆。

项目成果

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Matthew Joseph Potthoff其他文献

Matthew Joseph Potthoff的其他文献

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{{ truncateString('Matthew Joseph Potthoff', 18)}}的其他基金

Endocrine Regulation of Alcohol Intake
酒精摄入的内分泌调节
  • 批准号:
    10289389
  • 财政年份:
    2020
  • 资助金额:
    $ 59.07万
  • 项目类别:
Endocrine Regulation of Alcohol Intake
酒精摄入的内分泌调节
  • 批准号:
    9887298
  • 财政年份:
    2020
  • 资助金额:
    $ 59.07万
  • 项目类别:
Endocrine Regulation of Alcohol Intake
酒精摄入的内分泌调节
  • 批准号:
    10083683
  • 财政年份:
    2020
  • 资助金额:
    $ 59.07万
  • 项目类别:
Endocrine Regulation of Alcohol Intake
酒精摄入的内分泌调节
  • 批准号:
    10544296
  • 财政年份:
    2020
  • 资助金额:
    $ 59.07万
  • 项目类别:
Endocrine Regulation of Alcohol Intake
酒精摄入的内分泌调节
  • 批准号:
    10321634
  • 财政年份:
    2020
  • 资助金额:
    $ 59.07万
  • 项目类别:
Central Mechanisms Regulating Macronutrient Intake
调节大量营养素摄入的中心机制
  • 批准号:
    10266052
  • 财政年份:
    2019
  • 资助金额:
    $ 59.07万
  • 项目类别:
Central Mechanisms Regulating Macronutrient Intake
调节大量营养素摄入的中心机制
  • 批准号:
    9974289
  • 财政年份:
    2019
  • 资助金额:
    $ 59.07万
  • 项目类别:
Regulation of Energy Homeostasis by FGF21
FGF21 对能量稳态的调节
  • 批准号:
    10118923
  • 财政年份:
    2015
  • 资助金额:
    $ 59.07万
  • 项目类别:
Regulation of Energy Homeostasis by FGF21
FGF21 对能量稳态的调节
  • 批准号:
    10266143
  • 财政年份:
    2015
  • 资助金额:
    $ 59.07万
  • 项目类别:
Regulation of Energy Homeostasis by FGF21
FGF21 对能量稳态的调节
  • 批准号:
    10450711
  • 财政年份:
    2015
  • 资助金额:
    $ 59.07万
  • 项目类别:

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