Severe acute respiratory syndrome coronavirus 2 infection leads to Tau pathological signature in neurons

Cristina Di Primio; Paola Quaranta; Marianna Mignanelli; Giacomo Siano; Matteo Bimbati; Arianna Scarlatti; Carmen Rita Piazza; Piero Giorgio Spezia; Paola Perrera; Fulvio Basolo; Anello Marcello Poma; Mario Costa; Mauro Pistello; Antonino Cattaneo

doi:10.1093/pnasnexus/pgad282

Severe acute respiratory syndrome coronavirus 2 infection leads to Tau pathological signature in neurons

PNAS Nexus. 2023 Sep 19;2(9):pgad282. doi: 10.1093/pnasnexus/pgad282. eCollection 2023 Sep.

Authors

Cristina Di Primio¹, Paola Quaranta^{1

2}, Marianna Mignanelli³, Giacomo Siano³, Matteo Bimbati^{3

4}, Arianna Scarlatti³, Carmen Rita Piazza^{2

5}, Piero Giorgio Spezia², Paola Perrera², Fulvio Basolo⁶, Anello Marcello Poma⁶, Mario Costa¹, Mauro Pistello^{2

7}, Antonino Cattaneo³

Affiliations

¹ Institute of Neuroscience, Italian National Research Council (CNR), Pisa 56124, Italy.
² Retrovirus Center, Virology Section, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56100, Italy.
³ Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore di Pisa, Pisa 56126, Italy.
⁴ Department of Biotechnology, University of Verona, Verona 37134, Italy.
⁵ Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy.
⁶ Department of Surgical, Medical and Molecular Pathology, University Hospital of Pisa, Pisa 56124, Italy.
⁷ Virology Unit, Pisa University Hospital, Pisa 56100, Italy.

Abstract

COVID-19 has represented an issue for global health since its outbreak in March 2020. It is now evident that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in a wide range of long-term neurological symptoms and is worryingly associated with the aggravation of Alzheimer's disease. Little is known about the molecular basis of these manifestations. Here, several strain variants were used to infect SH-SY5Y neuroblastoma cells and K18-hACE C57BL/6J mice. The Tau phosphorylation profile and aggregation propensity upon infection were investigated on cellular extracts, subcellular fractions, and brain tissue. The viral proteins spike, nucleocapsid, and membrane were overexpressed in SH-SY5Y cells, and the direct interaction and effect on Tau phosphorylation were checked using immunoblot experiments. Upon infection, Tau is phosphorylated at several pathological epitopes associated with Alzheimer's disease and other tauopathies. Moreover, this event increases Tau's propensity to form insoluble aggregates and alters its subcellular localization. Our data support the hypothesis that SARS-CoV-2 infection in the central nervous system triggers downstream effects altering Tau function, eventually leading to the impairment of neuronal function.

Keywords: COVID-19; SARS-CoV-2; Tau; neuro-COVID; phospho-Tau.