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.

项目概要/摘要与受损、错误折叠和聚集蛋白质积累相关的蛋白质稳态丧失是衰老和许多与年龄相关的神经退行性疾病的特征。可能部分是由与年龄相关的自噬功能障碍驱动的，该功能障碍建立了一个前驱过程，导致越来越多的证据表明，蛋白质稳态下降和随后的神经变性减少。转录因子 EB (TFEB) 是自噬和溶酶体生物发生的主要调节因子，其活性可以是许多神经退行性疾病的基础，根据这些发现，我们进行了化学筛选。诱导 TFEB 的化学化合物的神经元细胞系我们鉴定了一系列诱导 TFEB 的化合物。 TFEB 及其目标水平远远超过我们领先的经典 TFEB 诱导剂雷帕霉素。化合物“C1”在多种蛋白毒性疾病模型中进行了测试，包括线虫 C. 线虫、体外人类神经元 tau 蛋白病模型以及帕金森病体内小鼠模型 (PD) 与自噬流的升高相结合，发现该化合物可以防止形成神经毒性蛋白质聚集并增强线粒体功能。分析表明，C1 通过充当核激素受体 DAF 的“反向激动剂”来诱导 TFEB 12/FXR，通过使用已知的 DAF-12/FXR 调制器进行验证，尽管 FXR 以其能力而闻名。它在肝脏和肠道中发挥作用，维持脂质稳态，最近被证明存在于大脑神经元中尽管它在这里的作用目前尚未被探索，但我们的结果凸显了一种以前未表征的新颖作用。 FXR-TFEB 信号介导的自噬在与年龄相关的神经退行性疾病中的应用。结果，我们发现神经元 FXR 机制可调节 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靶点，包括为了检验这一假设，我们建议确定：(1) FXR 抑制结果。下游 TFEB 信号传导，引发 AD 和受影响神经元内神经元自噬的增加 (2) 防止 AD 相关病理的后续发展拟议的研究包括分析。在人类 iPSC 衍生的神经元和体内 AD 小鼠模型的脑组织中询问特征与人类疾病相关，包括线粒体缺陷、Aβ 和 tau 蛋白的逐渐发展神经病理学、突触完整性丧失以及小鼠认知功能障碍。