Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy.
Department of Surgery Medicine Dentistry and Morphological Sciences with an Interest in Transplant Oncology, University of Modena and Reggio Emilia, Modena, Italy.
Exp Neurol. 2024 Oct;380:114908. doi: 10.1016/j.expneurol.2024.114908. Epub 2024 Jul 31.
The COVID-19, caused by SARS-CoV-2, first affects the respiratory tract but evidence is emerging that the virus, reaching the central nervous system (CNS), can lead to severe neurological disorders. In particular, CoV infection could cause an acceleration of the neurodegenerative process. On the other hand, patients diagnosed with Alzheimer's disease (AD) develop more serious forms of COVID-19 with worse relapses. Therefore, understanding the connection between the two pathologies, AD and infection by coronavirus, could help in the development of new therapeutic approaches to counter them. We used the SH-SY5Y cell line differentiated into neurons, as widely used in studies of AD if supplemented with exogenous fibrillary β-amyloid (Aβ). As a glial counterpart, human microglia (HMC3) and astrocytic (D54MG) cell lines were used to create co-cultures with neurons via transwell systems. In these experimental models, we generated infection with the Human Coronavirus OC43 (HCoV-OC43), a low-risk model of SARS-CoV-2. Our results suggest that the infection by HCoV-OC43 leads to a neurotoxic effect not depending on an already present event of Aβ deposition. Indeed, unlike microglia, neurons and even more astrocytes are susceptible to CoV infection and, although the infection does not show a cytotoxic effect in the neurons in the first few days, significant alterations at a biochemical and morphological level have been observed, suggesting that the neurons are reacting to a stressful condition, including the prodromal and neurodegenerative features of AD. Interestingly, the interaction of infected astrocytes with the neurons resulted in the manifestation of signs of neurodegeneration, such as amyloid-beta deposition. By using exogenous fibrillary Aβ, as an AD in vitro model, our data suggest that there is an aggravating effect both on the infection itself and on the neurological disease progression. In conclusion, the results of this study suggest a causal interplay between HCoV-OC43 and neurological diseases and demonstrate that the co-presence of different CNS cell populations is the necessary condition to study the pathogenic effects in vitro as a whole.
由 SARS-CoV-2 引起的 COVID-19 最初影响呼吸道，但有证据表明，该病毒进入中枢神经系统 (CNS) 后，可能导致严重的神经紊乱。特别是，CoV 感染可能导致神经退行性过程加速。另一方面，诊断为阿尔茨海默病 (AD) 的患者患上 COVID-19 的更严重形式，且病情恶化更严重。因此，了解这两种病理学（AD 和冠状病毒感染）之间的联系，有助于开发针对它们的新治疗方法。我们使用分化为神经元的 SH-SY5Y 细胞系，如在 AD 研究中广泛使用的，如果补充外源性纤维状 β-淀粉样蛋白 (Aβ)。作为神经胶质细胞的对应物，我们使用人小胶质细胞 (HMC3) 和星形胶质细胞 (D54MG) 细胞系通过 transwell 系统与神经元建立共培养物。在这些实验模型中，我们生成了人类冠状病毒 OC43 (HCoV-OC43) 的感染，这是 SARS-CoV-2 的低风险模型。我们的结果表明，HCoV-OC43 的感染会导致神经毒性效应，而不依赖于已经存在的 Aβ沉积事件。事实上，与小胶质细胞不同，神经元甚至更多的星形胶质细胞易受 CoV 感染，尽管感染在最初几天内不会对神经元产生细胞毒性作用，但在生化和形态水平上观察到了显著的改变，表明神经元正在对一种应激状态做出反应，包括 AD 的前驱和神经退行性特征。有趣的是，感染的星形胶质细胞与神经元的相互作用导致了神经变性的迹象，如淀粉样蛋白-β沉积。通过使用外源性纤维状 Aβ作为 AD 的体外模型，我们的数据表明，它对感染本身和神经退行性疾病的进展都有加重作用。总之，这项研究的结果表明 HCoV-OC43 与神经疾病之间存在因果关系，并证明不同中枢神经系统细胞群体的共存是体外研究整体致病作用的必要条件。
