Ectodermal-neural cortex 1 and neuronal vulnerability to tau pathology in Alzheimer's disease

阿尔茨海默病中外胚层神经皮质 1 和神经元对 tau 病理学的脆弱性

• 批准号: 10578846
• 负责人: Hongjun Fu
• 金额: $ 48.2万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578846
• 关键词: Acceleration; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Autophagocytosis; Autophagosome; Autopsy; Bioinformatics; Brain; Cell Nucleus; Cells; Cerebrum; Cognition; Cytoplasm; Data; Data Set; Functional disorder; Genes; Genomics; Homeostasis; Human; Huntington gene; Impairment; In Vitro; Individual; Link; LoxP-flanked allele; Maps; Measures; Mediating; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Organoids; Pathogenesis; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Prevention; Primary Brain Neoplasms; Proteins; RNA; Regulation; Role; Signal Pathway; Specimen; Tertiary Protein Structure; Testing; Transcript; Transgenic Mice; Work; brain cell; brain tissue; cell type; cohort; design; endoplasmic reticulum stress; entorhinal cortex; excitatory neuron; experimental study; expression vector; genetic signature; in vivo; in vivo Model; inhibition of autophagy; insight; knock-down; mind control; mutant; neoplastic cell; nervous system disorder; neural; neurotoxicity; new therapeutic target; novel; nuclear factor-erythroid 2; overexpression; prevent; promoter; proteostasis; single nucleus RNA-sequencing; tau Proteins; tau aggregation; tau mutation; transcriptomics

In many neurological diseases, specific subsets of neurons are more sensitive to dysfunction and degeneration than others. In Alzheimer’s disease (AD), excitatory (EX) neurons are preferentially vulnerable to tau pathology which defines the pathogenesis and progression of dysfunction in AD. Understanding the molecular origins of selective neuronal vulnerability is of fundamental importance for all of the neurodegenerative diseases including AD. Using single-nucleus RNA-seq dataset analysis and weighted gene co-expression network analysis of the transcriptomic signatures of different cell types from non-AD cases, we identified novel subproteome gene signatures in EX neurons that may serve as potential master regulators of selective neuronal and regional vulnerability to tau pathology in early AD. The ectodermal-neural cortex 1 (ENC1) is one such potential master regulator. Although the role of ENC1 in AD has not been thoroughly investigated, if it functions as a master regulator as predicted by bioinformatics analysis, it may be possible to regulate ENC1 levels to control tau pathology and thwart the onset or progression of AD. Preliminary analysis of human entorhinal cortex from AD and control brain specimens has revealed that ENC1 is enriched in the nucleus of EX neurons in control brains, while cytoplasmic ENC1 levels are elevated within neurons that show accumulated pathological tau species in AD specimens. The interaction between ENC1 and tau correlates directly with levels of pathological tau. Furthermore, forced overexpression of ENC1 mainly in the cytoplasm increases tau aggregation and seeding activity, whereas knockdown of ENC1 reduces these pathological changes. ENC1 has been shown to increase the neurotoxicity of mutant huntingtin under ER stress through the interaction with p62 and the inhibition of autophagy flux. Our new data also show ENC1 overexpression increases pathological tau accumulation, p62 puncta formation and autophagy dysfunction, implicating impairment of p62-mediated autophagy as a mechanism underlying the cytoplasmic accumulation of ENC1 and pathological tau in neurons. Based on these preliminary data, we hypothesize that cytoplasmic ENC1 contributes to the vulnerability of EX neurons to tau pathology, and that reducing ENC1 in EX neurons will enhance the autophagy pathway thereby protecting these EX neurons from selective neurodegeneration in AD. To test this hypothesis, this proposal will (1) determine the effect of ENC1 on tau aggregation and propagation in human cerebral organoids; (2) investigate the role of ENC1 in autophagy pathway and if this pathway is involved in ENC1-induced tau aggregation and propagation in vitro; and (3) determine if cell-type specific manipulation of ENC1 affects neuronal autophagy, AD pathology and cognition in vivo. The proposed studies will provide mechanistic insight into the role of ENC1 as a master regulator of tau homeostasis and will also provide greater insight for developing novel therapeutics targeting ENC1-dependent pathways to prevent, treat or delay the neurodegeneration in AD. Furthermore, this work will elucidate novel mechanisms underlying selective neuronal vulnerability in AD.

在许多神经系统疾病中，特定的神经元亚群对功能障碍和变性更敏感 than others.在阿尔茨海默病（AD）中，兴奋性（EX）神经元优先易受tau病理损伤。 其定义了AD中功能障碍的发病机制和进展。了解分子起源 选择性神经元脆弱性对于所有神经变性疾病都是至关重要的 AD.使用单核RNA-seq数据集分析和加权基因共表达网络分析， 转录组签名的不同类型的细胞从非AD病例，我们确定了新的亚蛋白质组基因 在EX神经元的签名，可以作为潜在的主调节器的选择性神经元和区域 在早期AD中对tau病理学的易感性。外胚层-神经皮层1（ENC 1）就是这样一个潜在的主控细胞 调节器尽管ENC 1在AD中的作用尚未被彻底研究，但如果它作为主基因发挥作用， 如生物信息学分析所预测的，可能通过调节ENC 1水平来控制tau蛋白 病理学和阻止AD的发作或进展。AD患者内嗅皮层的初步分析 并且对照脑样本显示ENC 1在对照脑中的EX神经元的核中富集， 而细胞质ENC 1水平在神经元内升高，这些神经元显示出累积的病理性tau种类， AD标本。ENC 1和tau之间的相互作用与病理性tau水平直接相关。 此外，ENC 1主要在细胞质中的强制过表达增加了tau蛋白的聚集和播种。 活性，而ENC 1的敲低减少了这些病理变化。ENC 1已被证明增加 突变亨廷顿蛋白在内质网应激下通过与p62相互作用和抑制 自噬通量我们的新数据还表明ENC 1过表达增加了病理性tau蛋白积累，p62 斑点形成和自噬功能障碍，暗示p62介导的自噬损伤是一种 神经元中ENC 1和病理性tau蛋白的细胞质积累的潜在机制。基于这些 根据初步数据，我们假设细胞质ENC 1有助于EX神经元的脆弱性， tau病理学，并且降低EX神经元中的ENC 1将增强自噬途径，从而 保护这些EX神经元免于AD中的选择性神经变性。为了验证这一假设， 将（1）确定ENC 1对人脑类器官中tau聚集和传播的影响;（2） 研究ENC 1在自噬通路中的作用，以及该通路是否参与ENC 1诱导的tau蛋白 体外聚集和增殖;和（3）确定ENC 1的细胞类型特异性操作是否影响 神经元自噬、AD病理学和体内认知。拟议的研究将提供机制的见解 研究ENC 1作为tau稳态的主要调节因子的作用，也将为开发新的研究提供更深入的见解。 靶向ENC 1依赖性通路以预防、治疗或延迟AD中的神经变性的新疗法。 此外，这项工作将阐明新的机制，潜在的选择性神经元的脆弱性在AD。