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

摘要/摘要 嗅觉障碍被认为是阿尔茨海默病(AD)和痴呆的前驱综合征。然而， 认知障碍发作前导致AD患者嗅觉障碍的分子和细胞机制 下降趋势仍不得而知。在这里，我们基于我们最近对SARS-CoV-2机制的观察 介导性嗅觉丧失解释蛋白质如何在一小部分感觉神经元中错误折叠和聚集 会导致嗅觉系统在气味检测方面出现广泛的缺陷。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是 病毒极其脆弱，对SARS-CoV-2感染引发的炎症信号作出反应后迅速消散。 引人注目的是，我们在AD小鼠模型中的初步数据也揭示了类似的核结构破坏 它也表现出与感染SARS-CoV-2的仓鼠相似的炎症特征。基于这些 这两种情况有惊人的相似之处，我们建议调查一个具有挑衅性的前提，即嗅觉障碍 阿尔茨海默病是由基因组OR区段的非细胞自主破坏引起的，因此，OR下调。 我们将通过实验测试与AD相关的人类APP突变体的零星表达是否会改变 幼稚嗅觉神经元染色体间相互作用的模式，我们将探索人类血清 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 新冠肺炎。最后，扩展我们在分析嗅觉神经元的核结构方面的最新技能 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 病人。我们提出的实验有可能揭示新的分子和细胞机制 AD病理学的传播，并使分子诊断学的发展能够预测 迟发性嗅觉功能障碍是AD的前驱症状。

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.