Non-cell autonomous disruption of genomic interactions as a cause of dementia

基因组相互作用的非细胞自主破坏是痴呆的原因

• 批准号: 10712217
• 负责人: Stavros Lomvardas
• 金额: $ 41.12万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712217
• 关键词: 2019-nCoV; Administrative Supplement; Afferent Neurons; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Anosmia; Architecture; Autopsy; COVID-19; Chemicals; Data; Dementia; Detection; Development; Disease; Event; Exhibits; Fractionation; Functional disorder; Genomics; Hamsters; Human; Impaired cognition; In Situ; Indiana; Inflammatory; Inflammatory Response; Link; Mediating; Modeling; Molecular; Mus; Mutation; Nasal Epithelium; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic Symptoms; Neurons; Nose; Nuclear; Odors; Olfactory Epithelium; Olfactory Pathways; Olfactory dysfunction; Parkinson Disease; Patients; Pattern; Peripheral; Population; Property; Proteins; Receptor Down-Regulation; Reporting; SARS-CoV-2 infection; Serum; Signal Pathway; Signal Transduction; Smell Perception; Sorting; South African; Symptoms; Techniques; Testing; Veins; Virus Diseases; Work; experimental study; extracellular; familial Alzheimer disease; inducible Cre; molecular diagnostics; mouse model; mutant; novel; novel diagnostics; novel therapeutics; olfactory receptor; olfactory sensory neurons; prognostic tool; promoter; protein aggregation; protein misfolding; receptor downregulation; receptor expression; response; skills; transcriptome sequencing

Summary/Abstract Olfactory dysfunction is considered a prodrome syndrome of Alzheimer’s Disease (AD) and Dementia. Yet, the molecular and cellular mechanisms that cause olfactory deficits in AD patients before the onset of cognitive decline remain unknown. Here, we built upon our recent observations on the mechanisms of SARS-CoV-2 mediated anosmia to decipher how protein misfolding and aggregation in a small fraction of sensory neurons can cause widespread deficits in odor detection by the olfactory system. Our studies on hamsters and humans, revealed that interchromosomal genomic interactions required for olfactory receptor (OR) expression are extremely fragile and dissipate rapidly in response to inflammatory signals elicited by SARS-CoV-2 infection. Strikingly, similar disruption of nuclear architecture is revealed by our preliminary data in mouse models for AD which also exhibit similar inflammatory signatures with the SARS-CoV-2 infected hamsters. Based on these striking similarities between the two conditions, we propose to investigate the provocative premise that anosmia in AD is caused by non-cell autonomous disruption of genomic OR compartments and, thus, OR downregulation. We will experimentally test whether sporadic expression of human APP mutants linked to AD can change the patterns of interchromosomal interactions of naive olfactory neurons, and we will explore if the serum of human APP-expressing mice can alter the nuclear architecture of wild type neurons, mimicking our observations for COVID-19. Finally, expanding on our recent skills in analyzing the nuclear architecture of olfactory neurons from human autopsies, we will investigate whether similar changes are observed in human olfactory neurons of AD patients. Our proposed experiments have the potential to uncover novel molecular and cellular mechanisms of propagation of AD pathology, and to enable the development of molecular diagnostics that can predict whether late onset olfactory dysfunction is a prodrome of AD.

总结/摘要 嗅觉功能障碍被认为是阿尔茨海默病（AD）和痴呆的前驱症状综合征。然而 AD患者在认知功能障碍发作前引起嗅觉障碍的分子和细胞机制 下降仍然未知。在这里，我们建立在我们最近对SARS-CoV-2机制的观察基础上， 介导的嗅觉丧失，以破译蛋白质如何错误折叠和聚集在一小部分感觉神经元 会导致嗅觉系统对气味的检测普遍不足。我们对仓鼠和人类的研究， 揭示了嗅觉受体（OR）表达所需的染色体间基因组相互作用， 在SARS-CoV-2感染引发的炎症信号的反应中，它们非常脆弱并迅速消散。 引人注目的是，我们在AD小鼠模型中的初步数据揭示了类似的核结构破坏 其也表现出与SARS-CoV-2感染的仓鼠相似的炎症特征。基于这些 这两种情况之间惊人的相似之处，我们建议调查的挑衅性前提，嗅觉丧失 在AD中，由基因组OR区室的非细胞自主破坏引起，因此，OR下调。 我们将通过实验测试与AD相关的人APP突变体的零星表达是否可以改变AD的发病机制。 幼稚嗅觉神经元的染色体间相互作用的模式，我们将探讨是否人的血清 表达APP的小鼠可以改变野生型神经元的核结构，模拟我们对 2019冠状病毒病。最后，扩展我们最近在分析嗅觉神经元核结构方面的技能， 人类尸检，我们将调查是否在AD的人类嗅觉神经元中观察到类似的变化 患者我们提出的实验有可能揭示新的分子和细胞机制， 传播AD病理，并使分子诊断的发展，可以预测是否 迟发性嗅觉功能障碍是AD的前驱症状。