Neuronal FXR as a potential therapeutic target for Alzheimer's disease

神经元 FXR 作为阿尔茨海默病的潜在治疗靶点

基本信息

批准号：
10374862
负责人：
Julie Kay Andersen
金额：
$ 62.32万
依托单位：
BUCK INSTITUTE FOR RESEARCH ON AGING
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374862
关键词：
Affect Age Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Autophagocytosis Biochemical Biogenesis Brain Brain region Caenorhabditis elegans Cell Line Characteristics Chemicals Collaborations Dementia Development Disease Disease model Excision Functional disorder Genetic Genetic Transcription Homeostasis Human Impaired cognition In Vitro Induced pluripotent stem cell derived neurons Lead Lipids Liver Lysosomes Mediating Mitochondria Modeling Mus Nematoda Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Nuclear Hormone Receptors Parkinson Disease Pathologic Pathology Process Proteins Role Series Signal Transduction Sirolimus Synapses Tauopathies Testing age related age related neurodegeneration antagonist base brain tissue experimental study human disease human old age (65+)in vivo in vivo Model induced pluripotent stem cell mouse model neurodegenerative phenotype neuropathology neurotoxic novel prevent protein aggregation proteostasis proteotoxicity tau Proteins therapeutic target transcription factor

项目摘要

PROJECT SUMMARY / ABSTRACT Losses in protein homeostasis associated with accumulation of damaged, misfolded and aggregated proteins is a characteristic feature of aging and many age-related neurodegenerative diseases. We hypothesize that this may in part be driven by age-related dysfunctions in autophagy which establishes a prodromal process resulting in decreased protein homeostasis and subsequent neurodegeneration. Growing evidence suggests that reduced activity of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, could underlie many neurodegenerative diseases. Based on these findings, we conducted a chemical screen in a neuronal cell line for chemical compounds that induce TFEB. We identified a series of compounds that induce TFEB and its targets to levels far exceeding that produced by the classic TFEB inducer rapamycin. Our lead compound `C1' was tested across a wide range of proteotoxic disease models including in the nematode C. elegans, in in vitro human neuronal tauopathy models, and in an in vivo mouse model of Parkinson's disease (PD). In conjunction with elevations in autophagic flux, the compound was found to prevent the formation of neurotoxic proteins aggregates and enhanced mitochondrial function. Subsequent genetic and biochemical analysis shows that C1 induces TFEB by acting as a “reverse agonist” of the nuclear hormone receptor DAF- 12/FXR, validated via the use of known modulators of DAF-12/FXR. Although FXR is best known for its ability to act in the liver and gut to maintain lipid homeostasis, it has recently been shown to be present in brain neurons although its role in here is currently unexplored. Our results highlight a novel previously uncharacterized role for FXR-TFEB signaling-mediated autophagy in age-associated neurodegenerative diseases. Based on these results, we hypothesize that neuronal FXR mechanistically acts to modulate levels of TFEB-mediated autophagy and as such constitutes a novel target for the treatment of age-related neurodegenerative diseases including Alzheimer's disease (AD). To test this hypothesis, we propose to determine whether: (1) FXR inhibition results in downstream TFEB signaling, triggering an increase in neuronal autophagy within neurons affected in AD and (2) prevents subsequent development of established AD-related pathologies. Proposed studies include analyses in both human iPSC-derived neurons and in brain tissues from an in vivo AD mouse model to interrogate features associated with human disease including progressive development of mitochondrial deficits, Aβ and tau neuropathology, losses in synapse integrity, and in mice, cognitive dysfunction.

项目摘要 /摘要与受损，错误折叠和汇总蛋白的积累相关的蛋白质稳态损失是衰老和许多与年龄相关的神经退行性疾病的特征。我们假设这是可能部分由自噬中与年龄相关的功能障碍驱动，该功能障碍建立了前瞻性过程在蛋白质稳态减少和随后的神经变性中。越来越多的证据表明减少了转录因子EB（TFEB）的活性是自噬和溶酶体生物发生的主要调节剂基于许多神经退行性疾病。基于这些发现，我们在A中进行了化学屏幕影响TFEB的化合物的神经元细胞系。我们确定了一系列影响的化合物 TFEB及其目标的水平远远超过了经典的TFEB诱导剂雷帕霉素所产生的水平。我们的领导化合物“ C1”在包括线虫C的各种蛋白毒性疾病模型中进行了测试。秀丽隐杆线虫，体外人类神经元模型，在帕金森氏病的体内老鼠模型中（PD）。结合自噬通量的高程，发现该化合物可防止形成神经毒性蛋白聚集体并增强线粒体功能。随后的遗传和生化分析表明，C1通过充当核马受体DAF-的“反向激动剂”来诱导TFEB。 12/fxr，通过使用DAF-12/FXR的已知调节剂验证。尽管FXR以其能力而闻名在肝脏和肠道中作用以维持脂质稳态，最近已显示出存在于脑神经元中尽管目前尚未探索其在此处的作用。我们的结果突出了一个新颖的以前未表征的作用 FXR-TFEB信号传导介导的自噬在与年龄相关的神经退行性疾病中。基于这些结果，我们假设神经元FXR机械起作用可调节TFEB介导的自噬水平因此，构成了治疗与年龄相关的神经退行性疾病的新颖目标阿尔茨海默氏病（AD）。为了检验这一假设，我们建议确定是否：（1）FXR抑制作用结果在下游TFEB信号传导中，触发AD和AD和（2）防止随后发展已建立的广告相关病理。拟议的研究包括分析在人IPSC衍生的神经元和脑组织中，从体内AD小鼠模型到询问特征与人类疾病有关，包括线粒体缺陷的逐步发展，Aβ和TAU 神经病理学，突触完整性中的损失以及小鼠的认知功能障碍。