Infectious agents and Alzheimer's disease

SARS-CoV-2 Neuroinvasion, Inflammatory Neurodegeneration and Alzheimer's Disease

“…Viral and other microbial infections of the brain and CNS have long been known to contribute, amplify or propagate many of the same neuropathological, inflammatory and neurodegenerative changes as is observed over the entire AD continuum (see below; Lingor et al, 2022;Lukiw et al, 2022;Piekut et al, 2022;Sirin et al, 2022;Szabo et al, 2022). Emerging evidence indicates that both DNA and RNA viruses, such as the human double-stranded DNA (dsDNA) Herpes simplex type 1 and 2 (HSV-1, HSV-2), the human cytomegalovirus (HMCV), the Epstein-Barr virus (EBV), and the ssRNA viruses hepatitis C virus (HCV; Herpesviridae), human influenza A viruses (H1N1/H3N2; Orthomyxoviridae), Zika virus (ZIKVs; Flaviviridae), MERS-CoV (Coronaviridae), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; Coronaviridae) and a remarkably large number of bacteria of the genus Bacteroides, Borrelia, Chlamydia, Treponema, Porphyromonas, Prevotella, Tannerella, Fusobacterium, Aggregatibacter, Eikenella and Helicobacter, as well as several other eukaryotic parasites (e.g., Toxicara; Toxoplasma) or fungi (Aspergillus; Candida) and others have been implicated in the etiopathology of inflammatory neurodegenerative diseases including AD.…”

“…Emerging evidence indicates that both DNA and RNA viruses, such as the human double-stranded DNA (dsDNA) Herpes simplex type 1 and 2 (HSV-1, HSV-2), the human cytomegalovirus (HMCV), the Epstein-Barr virus (EBV), and the ssRNA viruses hepatitis C virus (HCV; Herpesviridae), human influenza A viruses (H1N1/H3N2; Orthomyxoviridae), Zika virus (ZIKVs; Flaviviridae), MERS-CoV (Coronaviridae), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; Coronaviridae) and a remarkably large number of bacteria of the genus Bacteroides, Borrelia, Chlamydia, Treponema, Porphyromonas, Prevotella, Tannerella, Fusobacterium, Aggregatibacter, Eikenella and Helicobacter, as well as several other eukaryotic parasites (e.g., Toxicara; Toxoplasma) or fungi (Aspergillus; Candida) and others have been implicated in the etiopathology of inflammatory neurodegenerative diseases including AD. There is also evidence that a syntrophic consortium of complex microorganisms together, known as biofilms, may be involved and additionally contribute to the neuropathology of AD, however the combination of SARS-CoV-2 invasion with other microbes has not been well studied (Chakravarthi and Joshi, 2021;Piekut et al, 2022;Protto et al, 2022). Importantly, all microbial infections of nervous tissues as described above contribute to the development of a microbialor viral-induced cytokine storm, a smoldering and progressive inflammatory neurodegeneration and the appearance of neurofibrillary tangles (NFT), amyloid aggregation and related amyloidogenic processes as are observed during the course of AD (Ball et al, 2013;Hosseini et al, 2021; Chidambaram et al, 2022;Chiner-Vives et al, 2022;Visco et al, 2022).…”

“…Interestingly, a pre-existing diagnosis of AD predicts the highest risk for COVID-19 yet found, driving the highest mortality rate amongst any classification of aged individuals (Nagu et al, 2020;Yu et al, 2021). Recent epidemiological and neurological studies also suggests that persons with COVID-19, and especially severely affected COVID-19 patients, may be predisposed to the development of neurodegenerative disorders that include AD due to latent viral effects on CNS structure, function and homeostasis (Mao et al, 2020;Pacheco-Herrero et al, 2021;Chung et al, 2022;Piekut et al, 2022;Piras et al, 2022;Radhakrishnan and Kandasamy, 2022;Stefanou et al, 2022).…”

“…2021; Vigasova et al, 2021;Choe et al, 2022;Lee et al, 2022;Lingor et al, 2022;Piekut et al, 2022;Protto et al, 2022;Sirin et al, 2022; Figure 1). These neuropathological features become more pronounced over the progression of the AD continuum.…”

“…Three broad phases of AD have been described-sometimes referred to as the AD continuumcategorized from pre-clinical AD (also known as "the prodromal period") to mild cognitive impairment (MCI) to mild, moderate and severe AD. This AD continuum is further characterized neuropathologically by 7 major changes within the brain: (i) by the appearance of hyperphosphorylated tau proteins organized into twisted neurofilament bundles that appear as NFT; (ii) by the accumulation of amyloid-beta (Aβ) peptides that aggregate as dense, insoluble lipoprotein deposits called 'amyloid' or 'senile' plaques (SP); (iii) by astrogliosis and glial cell proliferation; (iv) by alterations in the innate-immune response, increases in inflammatory signaling and the up-regulation of proinflammatory cytokine and other biomarkers; (v) by progressive cytoskeletal and synaptic disorganization culminating in brain cell atrophy, synaptic signaling disruption, neuronal cell death and progressive neurodegeneration (Alzheimer et al, 1995;Lane et al, 2018;Trejo-Lopez et al, 2021;Zhou et al, 2021;Bethlehem et al, 2022); (vi) by weakened gastro-intestinal (GI) tract, neurovascular and blood-brain barriers allowing the influx of viral, microbial and other neurotoxins into brain and CNS compartments; and (vii) by deficits in the innate-immune system (see below; Moir et al, 2018;Li et al, 2021;Vigasova et al, 2021;Piekut et al, 2022). The appearance or onset of these 7 major changes typically begins many years prior to when clinical cognitive and behavioral symptoms emerge over a typical AD time course of several decades, and is conducive to an elevated risk of both chronic inflammatory neurodegeneration and opportunistic microbial infection (Lane et al, 2018;Trejo-Lopez et al, 2021;Vigasova et al, 2021;Bethlehem et al, 2022;Choe et al, 2022).…”