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: 10342436
• 负责人: Hongjun Fu
• 金额: $ 48.72万
• 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/10342436
• 关键词: 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 analysis; Regulation; Role; Signal Pathway; Specimen; Tertiary Protein Structure; Testing; Transcript; Transgenic Mice; Work; base; 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; neurotoxicity; new therapeutic target; novel; nuclear factor-erythroid 2; overexpression; prevent; promoter; proteostasis; relating to nervous system; tau Proteins; tau aggregation; tau mutation; transcriptome sequencing; 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 比其他人更好。在阿尔茨海默病(AD)中，兴奋性(EX)神经元更容易受到tau病理的影响 它定义了AD功能障碍的发病机制和进展。对分子起源的理解 选择性神经元脆弱性对所有神经退行性疾病都是至关重要的，包括 广告。利用单核RNA-seq数据集分析和加权基因共表达网络分析 非阿尔茨海默病患者不同细胞类型的转录特征，我们鉴定了新的亚蛋白质组基因 EX神经元中的信号可能作为选择性神经元和区域的潜在主调节因子 AD早期对tau病理的易感性。外胚层-神经皮质1(Enc1)就是这样一个潜在的主宰。 调整器。虽然enc1在AD中的作用还没有得到彻底的研究，但如果它作为主控发挥作用 如生物信息学分析预测的那样，有可能通过调节enc1水平来控制tau 病理，并阻止AD的发生或进展。阿尔茨海默病患者内嗅皮层的初步分析 而对照组的大脑标本显示，ENC1在对照组大脑的EX神经元的核中丰富， 而神经细胞内细胞质ENC1水平升高，显示出病理性tau蛋白的积累。 AD标本。ENC1和tau之间的相互作用与病理tau的水平直接相关。 此外，主要在细胞质中强制过表达enc1会增加tau的聚集和播种。 而ENC1基因的敲除则减少了这些病理变化。ENC1已经被证明是增加的 突变型亨廷顿蛋白在内质网应激下与p62的相互作用及对其的抑制作用 自噬通量。我们的新数据还显示，ENC1的过度表达增加了病理性tau的积聚，p62 点状形成和自噬功能障碍，暗示p62介导的自噬作为一种 神经细胞内ENC1和病理性tau胞浆积聚的机制。基于这些 初步数据，我们假设胞质ENC1有助于EX神经元对 Tau病理，而减少ex神经元中的enc1将从而增强自噬途径 保护这些EX神经元免受AD时选择性神经变性的影响。为了检验这一假设，这项提议 将(1)确定enc1对tau在人脑器官中聚集和繁殖的影响；(2) 研究enc1在自噬途径中的作用以及该途径是否参与了enc1诱导的tau 体外聚集和繁殖；以及(3)确定ENC1的细胞类型特异性操作是否影响 神经元自噬、阿尔茨海默病的病理和体内认知。拟议的研究将提供机械论的见解。 Enc1作为tau动态平衡的主要调节者的作用，也将为开发 针对ENC1依赖通路的新疗法，以预防、治疗或延缓AD的神经变性。 此外，这项工作将阐明阿尔茨海默病选择性神经元脆弱性的新机制。