Infectious agents and Alzheimer's disease

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Individuals affected by the disease gradually lose their capacity for abstract thinking, understanding, communication and memory. As populations age, declining cognitive abilities will represent an increasing global health concern. While AD was first described over a century ago, its pathogenesis remains to be fully elucidated. It is believed that cognitive decline in AD is caused by a progressive loss of neurons and synapses that lead to reduced neural plasticity. AD is a multifactorial disease affected by genetic and environmental factors. The molecular hallmarks of AD include formation of extracellular $\beta$ amyloid (A $\beta$ ) aggregates, neurofibrillary tangles of hyperphosphorylated tau protein, excessive oxidative damage, an imbalance of biothiols, dysregulated methylation, and a disproportionate inflammatory response. Recent reports have shown that viruses (e.g., Herpes simplex type 1, 2, 6A/B; human cytomegalovirus, Epstein-Barr virus, hepatitis C virus, influenza virus, and severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), bacteria (e.g., Treponema pallidum, Borrelia burgdorferi, Chlamydia pneumoniae, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, Fusobacterium nucleatum, Aggregatibacter actinomycetemcmitans, Eikenella corrodens, Treponema denticola, and Helicobacter pylori), as well as eukaryotic unicellular parasites (e.g., Toxoplasma gondii) may factor into cognitive decline within the context of AD. Microorganisms may trigger pathological changes in the brain that resemble and/or induce accumulation of A $\beta$ peptides and promote tau hyperphosphorylation. Further, the mere presence of infectious agents is suspected to induce both local and systemic inflammatory responses promoting cellular damage and neuronal loss.

Here we review the influence of infectious agents on the development of AD to inspire new research in dementia based on these pathogens.

Keywords

Alzheimer's disease

Dementia

Cognitive decline

Virus

Bacteria

Parasite

Infectious agents

Figures

Fig. 1.

Previous article in this issue

Next article in this issue

Fig. 1.

The pathomechanism of virus-associated neurodegeneration. Herpes simplex virus 1 (HSV-1) resides in neurons and may induce aggregation of A $\beta$ in Alzheimer’s disease (AD) by various mechanisms, that may be facilitated by the presence of APOE E4 genotype. HSV-1 may affect turnover of amyloid precursor protein (APP) to produce more amyloid $\beta$ (A $\beta$ ), subsequently, viral glycoprotein B might serve as a primal starter for A $\beta$ aggregation. HSV-1 may also influence APP and tau protein phosphorylation mediated by calcium ions (Ca ${}^{2+}$ ). The process may be induced by viral kinases, that lead to neuronal degeneration. Furthermore, HSV-1 may activate plasma cells to produce immunoglobulins M (IgM), whose increased levels has been linked do AD pathology. Conversely, to HSV-1 human betaherpesvirus 6A/B (HHV-6A/B) has the ability to affect both astrocytes and neurons. HHV-6 infection may reduce autophagy and lead to increased A $\beta$ accumulation and tau protein hyperphosphorylation. Moreover, glia under influence of HHV-6 secrete interleukin-6 (IL-6) and interleukin-8 (IL-8), whose excessive levels may promote neuroinflammation. Subsequently, cytomegalovirus infection has been associated with increase of immunoglobulins G (IgG) production, associated with future cognitive impairment. Similar systemic response may be induced by hepatitis C virus (HCV) infection, that stimulates production of interferon-1 (IFN), followed by overproduction of 25-hydroxycholesterol (25-OHC) and release of interleukin-1 $\beta$ by microglia, that lead to inflammatory response and neuronal loss. Respiratory viruses, including influenza virus H5N1 may also play role in AD pathology. H5N1 virus express A $\beta$ -like hemagglutinin, that promotes A $\beta$ aggregation and enhances proration of neurons, that lead to cellular damage and apoptosis. Conversely, influenza virus H1N1 is not neurotropic and promote neurodegeneration via reduction of neurotrophic factors: BDNF and GDNF, followed by activation of microglia and neuroinflammation. Analogically, SARS-CoV-2 virus does not damage the neurons per se, but enhances inflammatory response that promotes neuronal death and thus cognitive impairment.

1 of 3

J. Integr. Neurosci. Print ISSN 0219-6352 Electronic ISSN 1757-448X