Bugs in the Brain? An Infectious Etiology for Alzheimer's Disease
Location
Philadelphia, PA
Start Date
1-5-2024 1:00 PM
End Date
1-5-2024 4:00 PM
Description
Background
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the world with approximately 55 million people currently diagnosed. Much research has identified pathologic features of the disease, but our understanding of causation is still lacking. A current evidence-based hypothesis proposes that certain infectious agents initiate the neurodegeneration consistent with dementia, specifically AD. Two such infectious agents correlated to AD pathogenesis are Chlamydia pneumoniae (Cpn), a respiratory obligate intracellular bacterium, and SARS-CoV-2, the respiratory coronavirus responsible for the COVID-19 pandemic. Characteristics of both organisms may predispose susceptible populations to infection and disease manifestations. This review superimposes key characteristics common to both organisms that may lead to the pathogenesis of AD.
Methods
A literature search through PubMed and Google Scholar focused on primary, peer-reviewed articles from 1998 to the present. Cross reference evaluated Cpn’s and SARS-CoV-2’s association with AD. Our focus included the following features: genetic risk with expression of ApoEε4, structural/functional aspects of the infectious processes, biomarkers common to Cpn, SARS-CoV-2, and AD (CCL2, NRP1, and IL-6), and the resultant neuroinflammation.
Results
As respiratory pathogens, both Cpn and SARS-CoV-2, can use the olfactory neuroepithelium as an entry point to infect the brain proper. Further, ApoEε4 expression (an AD risk factor) appears to increase susceptibility to Cpn and SARS-CoV-2 infections. Cpn is thought to bind to heparin sulfate proteoglycans for entry into mucosal cells. SARS-CoV-2 binds to epithelial ACE2 receptors (involved in the renin-angiotensin-aldosterone system) via its spike protein. Once inside the neuroepithelia, Cpn and SARS-CoV-2 may traffic to the olfactory bulbs. NRP1, an abundantly expressed cell surface receptor in AD brains, also potentiates SARS-CoV-2 infection. The SARS-CoV-2 spike protein, in conjunction with CCL2, a cytokine involved in chemoattraction (in the olfactory neuroepithelium and in Alzheimer’s astrocytes), co-stimulates macrophages, resulting in IL-6 cytokine release. Likewise, Cpn leads to an increase of CCL2 and IL-6 cytokine release, resulting in macrophage stimulation. The primary infection (of either Cpn or SARS-CoV-2) can lead to chronically elevated levels of IL-6 and can increase susceptibility to secondary infection(s).
Conclusions
Cpn and SARS-CoV-2 enter olfactory epithelial cells to bypass the blood brain barrier to gain direct entry to the brain leading to neuroinflammation. This neuroinflammation can become chronic without the presence of the organism and can contribute to the pathogenesis of AD. Ongoing and future studies will further dissect the infectious etiology as a potential causative and diagnostic factor for AD.
Embargo Period
5-23-2024
Bugs in the Brain? An Infectious Etiology for Alzheimer's Disease
Philadelphia, PA
Background
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the world with approximately 55 million people currently diagnosed. Much research has identified pathologic features of the disease, but our understanding of causation is still lacking. A current evidence-based hypothesis proposes that certain infectious agents initiate the neurodegeneration consistent with dementia, specifically AD. Two such infectious agents correlated to AD pathogenesis are Chlamydia pneumoniae (Cpn), a respiratory obligate intracellular bacterium, and SARS-CoV-2, the respiratory coronavirus responsible for the COVID-19 pandemic. Characteristics of both organisms may predispose susceptible populations to infection and disease manifestations. This review superimposes key characteristics common to both organisms that may lead to the pathogenesis of AD.
Methods
A literature search through PubMed and Google Scholar focused on primary, peer-reviewed articles from 1998 to the present. Cross reference evaluated Cpn’s and SARS-CoV-2’s association with AD. Our focus included the following features: genetic risk with expression of ApoEε4, structural/functional aspects of the infectious processes, biomarkers common to Cpn, SARS-CoV-2, and AD (CCL2, NRP1, and IL-6), and the resultant neuroinflammation.
Results
As respiratory pathogens, both Cpn and SARS-CoV-2, can use the olfactory neuroepithelium as an entry point to infect the brain proper. Further, ApoEε4 expression (an AD risk factor) appears to increase susceptibility to Cpn and SARS-CoV-2 infections. Cpn is thought to bind to heparin sulfate proteoglycans for entry into mucosal cells. SARS-CoV-2 binds to epithelial ACE2 receptors (involved in the renin-angiotensin-aldosterone system) via its spike protein. Once inside the neuroepithelia, Cpn and SARS-CoV-2 may traffic to the olfactory bulbs. NRP1, an abundantly expressed cell surface receptor in AD brains, also potentiates SARS-CoV-2 infection. The SARS-CoV-2 spike protein, in conjunction with CCL2, a cytokine involved in chemoattraction (in the olfactory neuroepithelium and in Alzheimer’s astrocytes), co-stimulates macrophages, resulting in IL-6 cytokine release. Likewise, Cpn leads to an increase of CCL2 and IL-6 cytokine release, resulting in macrophage stimulation. The primary infection (of either Cpn or SARS-CoV-2) can lead to chronically elevated levels of IL-6 and can increase susceptibility to secondary infection(s).
Conclusions
Cpn and SARS-CoV-2 enter olfactory epithelial cells to bypass the blood brain barrier to gain direct entry to the brain leading to neuroinflammation. This neuroinflammation can become chronic without the presence of the organism and can contribute to the pathogenesis of AD. Ongoing and future studies will further dissect the infectious etiology as a potential causative and diagnostic factor for AD.