SARS-CoV-2 generates amyloid in the cerebrospinal fluid

In a recent study published in bioRxiv* Prepress server, an international team of researchers has demonstrated amyloid buildup due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human cerebrospinal fluid (CSF).

The SARS-CoV-2 pandemic and the long-term neurological complications that resulted from patients, referred to as the prolonged coronavirus disease (COVID), have re-established interest in the relationship between viral infection and neurodegenerative brain disease. Whereas many viruses, including herpes simplex virus type 1 (HSV-1), can infect the central nervous system (CNS) and cause acute or chronic infections, a direct mechanical connection between viruses and the assembly of amyloid proteins – a characteristic A feature of many neurodegenerative diseases – it has proven difficult to identify.

The study: SARS-CoV-2 and HSV-1 stimulate amyloid aggregation in human cerebrospinal fluid.  Image Credit: nobeastsofierce / Shutterstock

Stady: SARS-CoV-2 and HSV-1 stimulate amyloid accumulation in human cerebrospinal fluid. Image Credit: nobeastsofierce / Shutterstock

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In this study, researchers demonstrated that the ex vivo accumulation of amyloid protein was caused by HSV-1 and SARS-CoV-2 inactivated ultraviolet (UV) radiation in human CSF.

The team incubated live HSV-1 and UV-inactivated SARS-CoV-2 with CSF obtained from healthy people to determine whether viral particles could induce the accumulation of amyloid proteins in a complex human biofluid. A thioflavin-T (ThT) assay in which ThT fluorescence was amplified upon binding to amyloid fibrils was used to track the ability of viruses to cause amyloid production. In addition, the team observed virus-induced amyloid formation in the cerebrospinal fluid using transmission electron microscopy (TEM).

Furthermore, the amyloid aggregates produced by the viruses were collected and purified in order to characterize the proteins present in the amyloid fractions. This was achieved by washing, centrifuging and dissolving the amyloid fraction in 99% formic acid after removing non-amyloid proteins concomitant with 4% sodium dodecyl sulfate (SDS).


The results of the study showed that the cerebrospinal fluid without adding virus showed no significant sign of increased amyloid accumulation over time. Whereas, CSF containing both viruses was able to cause the accumulation of amyloid protein in CSF. Moreover, a much weaker signal was produced by other controls, such as only non-virus-infected cellular media, which was consistent with that observed for isolated amyloidogenic proteins. CSF with added virus produced a fluorescence amplification of ThT that was significantly greater than all controls. On the surface of HSV-1 and SARS-CoV-2, the team observed the interaction of several fibrillar amyloid structures, suggesting surface catalytic nucleation (HEN) processes.

Regarding the proteins in untreated cerebrospinal fluid, proteomic analysis showed that a large number of proteins were enriched in virus-induced amyloid fractions. Compared with untreated CSF, 279 proteins were found to be enriched in virus-induced amyloid fractions. The amyloid fractions produced by both viruses contain more than 40% of the enriched proteins shared, while the amyloid fractions produced by HSV-1 contain 37%, and SARS-CoV-2 contains 23% unique proteins. The higher expression of some proteins in CSF near hypersaturating levels may make them more susceptible to aggregation stimuli, as evidenced by the significant overlap between clusters of the two virus-promoting proteins.

In plaques obtained from Alzheimer’s (AD) patients, the team detected 135 proteins, including beta-amyloid precursors like protein 1 (APLP1), 2-macroglobulin, apolipoprotein E (ApoE), and staphylococcus. In addition, proteins related to other amyloid diseases, such as transtretin (TTR) and vitronectin, as well as proteins associated with Parkinson’s disease (PD), including ceruloplasmin, 14-3-3, nucleolin, and phosphoglycerate kinase 1 (PGK-1) were observed. These results demonstrated that viral particles were able to induce amyloid accumulation of several proteins in human cerebrospinal fluid.


Study results showed that HSV-1 and SARS-CoV-2 stimulated a variety of proteins to aggregate in human cerebrospinal fluid. The study also showed that UVB inhibition did not eliminate the ability of viral particles to act as a surface stimulator for the amyloid nucleus. Therefore, given the important catalytic function that viruses can play in this process, the role of viruses as causative agents of protein accumulation in neurodegeneration needs to be re-evaluated. Given the SARS-CoV-2 epidemic, which has left many patients with long-lasting neurological symptoms after infection, it is crucial to understand the processes by which viruses can cause neurological problems.

*Important note

bioRxiv It publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behaviour, or be treated as established information.

Journal reference:

  • SARS-CoV-2 and HSV-1 stimulate amyloid aggregation in human CSF, Wanda Crist, Sebastian Capel, Georgios Mermelikas, Bjorn Evertson, Helena Sork, Safa Bazaz, Oscar Gustafsson, Michel J. Subkoviak, Eduardo i Cardenas, Viviana Villa, Roberta Ricciarelli, Johan K. Sandberg, Jonas Bergquist, Andrea Storchio, Per Sveningson, Taria Malm, Alberto J. Espai, Maria Bernalmalm, Anders Linden, Jonas Klingstrom, Samir Andalus, Karim Ezzat, bioRxiv 2022.09.15.508120, DOI: the

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