Unraveling the Complex Interplay Between COVID-19 and the Central Nervous System: Implications for Olfactory Dysfunction and Alzheimer’s Disease

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Coronavirus disease (COVID-19), caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2), continues to pose a significant global health challenge even after three years into the pandemic. As of December 2022, the World Health Organization (WHO) has reported a staggering 652 million confirmed cases and 6.7 million deaths.

One key aspect of the virus is its impact on the human respiratory system, though it also affects other organs, including the central nervous system (CNS). A notable symptom linked to COVID-19 is olfactory dysfunction, which has been widely reported and is a consistent indicator of SARS-CoV-2 infection. While most patients recover their sense of smell within 2-3 weeks, about 10-20% experience prolonged loss, lasting for months. This phenomenon also ties into the broader category of long-lasting effects post-infection, commonly referred to as “long COVID”.

The virus’s impact on the CNS has been a subject of much discussion. The olfactory mucosa (OM), located in the nasal cavity, is one of the first lines of defense against airborne pathogens and could be a potential entry point for the virus to the brain. Interestingly, research indicates that human olfactory sensory neurons show low expression of TMPRSS2 and ACE-2, key proteins for SARS-CoV-2 entry, contrary to sustentacular cells in the olfactory epithelium. These findings suggest that the olfactory pathway could be a significant route for CNS invasion by the virus.

Another critical aspect of this discussion is the link between COVID-19 and Alzheimer’s disease (AD), a prevalent CNS disorder. Olfactory dysfunction is a common symptom in several neurodegenerative diseases, including AD. Recent studies have shown that cells in the OM of individuals with AD exhibit changes similar to those observed in AD-affected brains.

The potential connection between viral infections, including SARS-CoV-2, and AD has been a topic of much debate. While an increased risk of COVID-19 has been observed in individuals with AD, it is still unclear how the virus might impact the onset or progression of AD. However, COVID-19 severe infections are associated with aging-related molecular features in the brain, and brains of COVID-19 patients have shown AD-like pathological features.

To investigate this further, a study was conducted using OM biopsies from cognitively healthy individuals and those with AD. These samples were used to model the human OM in a 3D, Air–liquid interface (ALI) culture system, exploring the effects of SARS-CoV-2 on these cells. This study aimed to understand how AD influences susceptibility to SARS-CoV-2 and to map the transcriptomic landscape of the infection in both healthy and diseased cells.

Discussion

Olfactory Mucosa and SARS-CoV-2 Infection: Insights from a Novel 3D In Vitro Model

Context and Background

The olfactory mucosa (OM), located at the rooftop of the nasal cavity, plays a crucial role in our interaction with the external environment. Its direct contact with inhaled air exposes it to various particles, including pathogens like the SARS-CoV-2 virus. Previous studies have confirmed SARS-CoV-2 infection in the OM, using ex vivo human olfactory biopsies from infected individuals [68, 69]. However, there is a limited understanding of the viral replication and pathophysiological processes in OM cells, especially in the context of neurological diseases like Alzheimer’s Disease (AD).

Novel 3D In Vitro Model of the OM

This study marks a significant advancement in addressing the knowledge gaps by developing a human-derived 3D in vitro model of the OM. Using human OM biopsies, we cultivated cell cultures in an air-liquid interface (ALI) that successfully mimicked the in vivo characteristics of the OM. These cultures provide an innovative platform to study viral infections, including the differential responses of OM cells from individuals with AD.

Key Findings and Insights
  • OM-ALI Cultures Characterization: Our 3D ALI cultures of the human OM, derived from both AD and cognitively healthy individuals, demonstrated the formation of pseudostratified epithelium and cilia-expressing cells. These cells formed a robust barrier, confirmed by trans-epithelial electrical resistance (TEER) measurements and expression of tight junction markers.
  • Transcriptomic Analysis and Alzheimer’s Disease: The OM-ALI cells derived from AD individuals exhibited a distinct transcriptomic profile from healthy controls. We identified significant differentially expressed genes (DEGs) linked to Alzheimer’s pathology, highlighting the integration of AD-associated pathways like integrin signaling and Wnt-signaling in these cells.
  • Viral Entry and Infection Mechanisms: The OM-ALI cultures expressed key receptors and proteins facilitating SARS-CoV-2 entry, such as ACE-2 and Neuropilin-1 (NRP-1). Our findings align with previous research demonstrating the susceptibility of non-neural cells in the OM, particularly sustentacular cells, to SARS-CoV-2 infection.
  • Impact of SARS-CoV-2 Infection on OM Cells: The infection of OM cells leads to a series of changes, including an upsurge in pro-inflammatory cytokines, which may impair olfactory function. Our data indicate that the infection affects both apical ciliary and non-neuronal epithelial cells.
  • Differential Responses in AD and Non-AD Cells: Interestingly, while the infectivity of SARS-CoV-2 was similar in OM cells from both AD and non-AD individuals, the cellular responses varied. AD cells exhibited distinct transcriptomic changes post-infection, suggesting potential differences in disease outcomes.
  • Virus Variants and Infectibility: Our research also delved into the infectibility of OM cells with different SARS-CoV-2 variants, observing a notable variance in the susceptibility of these cells to different strains.
  • Long-term Implications and Neurological Impact: The study also sheds light on the potential long-term impacts of SARS-CoV-2 infection in individuals with AD, particularly concerning the persistent changes in gene expression and their possible links to exacerbated AD pathology.
Conclusions and Future Directions

This comprehensive study introduces a groundbreaking patient-derived cell model that significantly enhances our understanding of COVID-19 pathogenesis, particularly in the context of pre-existing conditions like AD. While offering valuable insights, the study also recognizes its limitations, including the need to consider factors like host genetics, age, and ethnicity.

Future research should expand on the interaction between AD pathology and SARS-CoV-2, exploring the wider implications on the nose-brain axis and the potential for this model to test therapeutic interventions for COVID-19 and other emerging pathogens.


reference link : https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02979-4#Sec20

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