5. Amyloidogenesis and SARS-CoV-2
A meta-analysis describes that molecules associated with COVID-19, such as TNF, IFNG, STAT1, IL1β, IL6, and STAT3, mediate the increased production of APP (Amyloid Precursor Protein) in an indirect way [43]. Neuroinflammation occurs by mitochondrial dysfunction, endoplasmic reticulum stress, and loss of proteostasis and autophagy deficiency [44]. A study mapping the interactions between each viral protein and human proteome lends shows the interactions of SARS-CoV-2 proteins with human proteins from several aging-related pathways [45].
The amyloid beta peptide (Aβ) is strongly related to neurodegenerative diseases such as Alzheimer’s [46]. It is known that neurons release Aβ in response to a viral infection [47,48]. Previous studies have reported the anti-microbial activity of Aβ, and infection with the herpes simplex virus has been proposed to be involved in Aβ plaque formation [49-51]. Years ago the concept that this peptide exerts antiviral action by binding to the virus, for example, the HSV-1 or influenza virus to prevent cell attack, avoiding massive destruction of nervous tissue [47], was adopted. Several studies indicate that the coronavirus infection stimulates Aβ production. This peptide bind to spike and contrary to what occurs with HSV-1 or influenza virus, this interaction could increase the entry to host cell and viral replication [52]. To respect, Chiricosta demonstrated in a cohort of Alzheimer’s patients that there is an upregulation of this protein propitiating the viral replication, also, the viral gene expression and viral transcription have a very high score compared to the other gene in the cohort of COVID-19+Alzheimer patients [28].
Mechanistic links have been reported between COVID-19 and Alzheimer’s Disease (AD) [53]. Accumulation of amyloid plaques is associated with neurodegeneration, espetially in AD [54]. Aβ is synthesized in coronavirus infection conditions, and the carboxyl-terminal region of Aβ42 is the responsible region of interaction with spike protein. To respect, an internal sequence of HSV-1 glycoprotein B (gB) is homologous to the carboxyl-terminal region of the Aβ42 [55]. Some authors described that Aβ1-42 could strengthen the binding of the S1 from Spike of SARS-CoV-2 to ACE2 and increase the viral entry, in a SARS-CoV-2 pseudovirus infection model [52]. That information suggests that the binding of Aβ1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and the neurological severity post SARS-CoV-2 infection.
Tavassoli and co-workers suggest that the heparin-binding region of the SARS-CoV-2 spike protein has greater protein aggregation capacity than other proteins in the same category from different viruses. In this way, this peptide has a greater capacity to generate aggregates including the beta-amyloid peptide and toxic aggregates [53]. Other authors demonstrated that several peptides from the proteome of SARS-CoV-2 can act like amyloid peptides by the aggregation and toxic effect. A high release can promote the accumulation of these insoluble compounds, becoming neurotoxic compounds. It is known that the accumulation of amyloid beta peptide is a trigger of neurodegenerative diseases. It is known that SARS-CoV-2 can bind amyloid beta peptide [54], more specifically Aβ42 can bind Spike [57]. S1 subunit receptor binding domain (SARS-CoV-2 S1 RBD) binds to heparin and heparin binds to others proteins. Also, it is established that heparin binding accelerates the aggregation of the pathological amyloid proteins present in the brain. Moeover, SARS-CoV-2 S1 RBD binds to many aggregation-prone, heparin binding proteins including Aβ, a-synuclein, tau, prion, and TDP-43 RRM [56]. These findings could be the molecular explanation of why some studies hypothesize that patients who have suffered from COVID-19 are more likely to contract neurodegenerative diseases [30, 58].
As mentioned above, there is a lack evidence to show that the presence of SARS-CoV-2 has a direct influence on neurological damage in the CNS. However, all stress situations, that are well reported to be generated during the COVID-19 illness, are a trigger for the synthesis of amyloid beta peptide and accelerate the Aβ accumulation. Cellular stress causes Aβ synthesis by nerve cells. In addition, as previously demonstrated with other viruses, viral infection can promote Aβ synthesis. Although no literature that clearly explains how coronaviruses can directly stimulate Aβ peptide synthesis, there is evidence in recovered or deceased post-COVID individuals that there is a greater Aβ presence in infected groups compared to uninfected groups [59].