An agent-based model to investigate microbial initiation of Alzheimer’s via the olfactory system

Abstract

Background: Alzheimer's disease (AD) is a degenerative brain disease. A novel agent-based modelling framework was developed in NetLogo 3D to provide fundamental insights into the potential mechanisms by which a microbe (eg. Chlamydia pneumoniae) may play a role in late-onset AD. The objective of our initial model is to simulate one possible spatial and temporal pathway of bacterial propagation via the olfactory system, which may then lead to AD symptoms. The model maps the bacteria infecting cells from the nasal cavity and the olfactory epithelium, through the olfactory bulb and into the olfactory cortex and hippocampus regions of the brain. Results: Based on the set of biological rules, simulated randomized infection by the microbe led to the formation of beta-amyloid (Aβ) plaque and neurofibrillary (NF) tangles as well as caused immune responses. Our initial simulations demonstrated that breathing in C. pneumoniae can result in infection propagation and significant buildup of Aβ plaque and NF tangles in the olfactory cortex and hippocampus. Our model also indicated how mucosal and neural immunity can play a significant role in the pathway considered. Lower immunities, correlated with elderly individuals, had quicker and more Aβ plaque and NF tangle formation counts. In contrast, higher immunities, correlated with younger individuals, demonstrated little to no such formation. Conclusion:The modelling framework provides an organized visual representation of how AD progression may occur via the olfactory system to better understand disease pathogenesis. The model confirms current conclusions in available research but can be easily adjusted to match future evidence and be used by researchers for their own individual purposes. The goal of our initial model is to ultimately guide further hypothesis refinement and experimental testing to better understand the dynamic system interactions present in the etiology and pathogenesis of AD.

Therapeutic drug repositioning with special emphasis on neurodegenerative diseases: Threats and issues

“…Some viruses, like the herpes virus, can go dormant after the original infection and then reawaken decades later in elderly people, causing delayed harmful complications ( Nagarajan and Wilde, 2005 ). According to a 2020 study model, immunocompromised people who were exposed to C. pneumoniae through their noses developed Aβ plaque and NFTs in their olfactory cortex as well as in hippocampus ( Sundar et al, 2020 ). Thus antimicrobials such as Rifampicin, Amphotericin B, acyclovir, penciclovir, foscarnet etc.…”

The Use of Antimicrobial and Antiviral Drugs in Alzheimer’s Disease

“…C. pneumoniae , a respiratory pathogen, has specifically been suggested to enter the brain through the olfactory system, with its presence detected in the entorhinal cortex and hippocampal formation of AD patients [ 73 ]. A recent 2020 study model demonstrated that exposure to C. pneumoniae via the olfactory system was sufficient to induce Aβ plaque and NFT formation in the olfactory cortex and hippocampus of immunocompromised individuals [ 74 ]. This is further evidenced by Little et al, who found that intranasal inoculation of C. pneumoniae was sufficient to induce AD-like traits in mice [ 75 ].…”

“…It must be noted, however, that the association between infection and Aβ plaque formation is not consistent across all populations. For example, in the study previously mentioned by Sundar et al, younger and healthier individuals exposed to C. pneumoniae did not exhibit the same AB peptide and NFT formation as older and immunocompromised subjects [ 74 ]. Moreover, it has been observed that genetic discrepancies, especially in the APOE gene, influence one’s susceptibility to HSV-1 infection and subsequent AD development.…”

Lactoferrin as Immune-Enhancement Strategy for SARS-CoV-2 Infection in Alzheimer’s Disease Patients

“…In a healthy situation, BBB provides a selective barrier to the passage of cells and molecules into the brain; however, in a pathological situation, a compromised BBB can allow direct entry into the brain through the passage of blood to the CSF ( 23 , 24 ). Moreover, pathogens, including bacteria and viruses can bypass the BBB by entering via the olfactory system, because the nasal cavity connects the peripheral environment to brain regions such as the olfactory bulb, the entorhinal cortex and the hippocampus ( 47 ). SARS-CoV-2 infection is widespread in epithelial cells, particularly in the lungs, starting its invasion and entry into the respiratory tract.…”