Chlamydia pneumoniae and SARS-CoV-2 may contribute to Alzheimer’s disease pathogenesis through neuroinflammatory pathways, according to a recent study.
Researchers explored the potential connections between Chlamydia pneumoniae (Cpn) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the pathogenesis of Alzheimer's disease (AD). This comprehensive review, published in Frontiers in Aging Neuroscience, aimed to consolidate existing research and ensure a rigorous assessment of the evidence linking these infections to neurodegeneration.
Led by Alexa Romanella of the Department of Bio-Medical Sciences at the Center for Chronic Disorders of Aging, Philadelphia College of Osteopathic Medicine (PCOM), the researchers conducted a focused review of peer-reviewed original research and other review articles. Their methodology emphasized the investigation of genetic risk factors, particularly the expression of the apolipoprotein E allele 4 (APOEε4), and AD-associated biomarkers such as interleukin-6 (IL-6), chemokine ligand 2 (CCL2), and neuropilin-1 (NRP1). Furthermore, they meticulously examined the structural and functional aspects of the infectious processes and the subsequent neuroinflammatory responses.
The findings indicate that both Cpn and SARS-CoV-2 possess mechanisms for neurological entry. Both pathogens can infect the neuroepithelium of the olfactory system which provides a direct route to the brain. Cpn gains cellular entry by binding to heparan sulfate proteoglycans, whereas SARS-CoV-2 infects epithelial cells via interaction with angiotensin-converting enzyme 2 receptors. Within the neuroepithelium, these pathogens may then traffic to the olfactory bulbs.
The review also highlighted that NRP1, a receptor that is frequently elevated in AD, may enhance SARS-CoV-2 infection.
Both Cpn and SARS-CoV-2 can enter the systemic circulation and subsequently traverse the blood-brain barrier. Specifically, the SARS-CoV-2 spike protein, in conjunction with CCL2, costimulates macrophages, leading to the release of IL-6 cytokines. Similarly, Cpn infection also resulted in an increase in CCL2 and IL-6 cytokine release. Primary infection by either organism potentially leads to chronically elevated levels of IL-6 and subsequent susceptibility to secondary infections. Additionally, the presence of the host's APOEε4 allele appeared to increase susceptibility to both Cpn and SARS-CoV-2 infections.
These results suggest that neuroinflammation stemming from infection with one or both organisms, characterized by elevated levels of CCL2 and IL-6, contributes to AD pathogenesis. The researchers concluded that these infections might serve as significant risk factors for the development or progression of AD, especially within the context of aging and specific genetic predispositions.
They concluded, "future studies should explore how APOEε4 genotype cells as well as the APOEε4 protein are involved in the interaction between these microbes, and others such as HSV1, and host cells. Studies should also look into why cells that are APOEε4 positive and infected with SARS-CoV-2 are more compromised as compared to their APOEε4 negative counterparts."
The authors declared no conflicts of interest.
Source: Frontiers in Aging Neuroscience
