Role of Tau protein in long COVID and potential therapeutic targets

Abstract

IntroductionLong COVID is an emerging public health burden and has been defined as a syndrome with common symptoms of fatigue, shortness of breath, cognitive dysfunction, and others impacting day-to-day life, fluctuating or relapsing over, occurring for at least two months in patients with a history of probable or confirmed SARS CoV-2 infection; usually three months from the onset of illness and cannot be explained by an alternate diagnosis. The actual prevalence of long-term COVID-19 is unknown, but it is believed that more than 17 million patients in Europe may have suffered from it during pandemic.PathophysiologyCurrently, there is limited understanding of the pathophysiology of this syndrome, and multiple hypotheses have been proposed. Our literature review has shown studies reporting tau deposits in tissue samples of the brain from autopsies of COVID-19 patients compared to the control group, and the in-vitro human brain organoid model has shown aberrant phosphorylation of tau protein in response to SARS-CoV-2 infection. Tauopathies, a group of neurodegenerative disorders with the salient features of tau deposits, can manifest different symptoms based on the anatomical region of brain involvement and have been shown to affect the peripheral nervous system as well and explained even in rat model studies. Long COVID has more than 203 symptoms, with predominant symptoms of fatigue, dyspnea, and cognitive dysfunction, which tauopathy-induced CNS and peripheral nervous system dysfunction can explain. There have been no studies up till now to reveal the pathophysiology of long COVID. Based on our literature review, aberrant tau phosphorylation is a promising hypothesis that can be explored in future studies. Therapeutic approaches for tauopathies have multidimensional aspects, including targeting post-translational modifications, tau aggregation, and tau clearance through the autophagy process with the help of lysosomes, which can be potential targets for developing therapeutic interventions for the long COVID. In addition, future studies can attempt to find the tau proteins in CSF and use those as biomarkers for the long COVID.

Exploring the Pathophysiology of Long COVID: The Central Role of Low-Grade Inflammation and Multisystem Involvement

“…Another aspect of canonical inflammation in LC, which was not included in the aims and objectives of our study, is considering LC as a risk factor for the onset of various inflammatory diseases or the progression of existing inflammatory diseases [ 323 , 324 , 325 , 326 , 327 ]. This primarily concerns immune-dependent diseases, whose association has been established, namely various allergic, autoimmune, and infectious diseases, but also should be taken into account in other pathological conditions as well [ 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 ,…”

“…Evidence also suggests that prior SARS-CoV-2 infection may facilitate the emergence or acceleration of canonical neurodegenerative diseases [ 234 , 235 , 236 , 237 ]. Research indicates that tau protein accumulation, a hallmark of neurodegenerative diseases and to a lesser extent in LC, is characteristic [ 238 , 239 ]. Therefore, further research is essential to definitively determine the role of virus-induced neuroparainflammation in the pathogenesis of ME/CFS, particularly in the context of its relationship with LC.…”

Investigating the structural network underlying brain-immune interactions using combined histopathology and neuroimaging: a critical review for its relevance in acute and long COVID-19

“…However, the mechanism underlying this association remains unclear ( 74 ). Another lesson learned by studying neurodegeneration in MS, AD and Parkinson’s disease (PD) that may bear insight in approaching Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the relevance of assessing in the cerebrospinal fluid (CSF) inflammatory biomarkers ( 11 ) or other potential biomarkers for COVID-19 such as tau ( 77 ). This may also be important information in reasoning on diagnosis and prognosis as well as such aspects as disease activity and response to treatment ( 11 ).…”

“…This process is carried out by extracellular micro-vesicles (EVs) or “exosomes”. Autopsy studies have shown tau deposits in brain tissue of COVID-19 patients ( 77 ). In addition, EVs containing tau are also present in cerebrospinal fluid and plasma of patients with mild AD and frontotemporal dementia (FTD) ( 77 , 81 ).…”

“…Autopsy studies have shown tau deposits in brain tissue of COVID-19 patients ( 77 ). In addition, EVs containing tau are also present in cerebrospinal fluid and plasma of patients with mild AD and frontotemporal dementia (FTD) ( 77 , 81 ). Nevertheless, regarding the relationship between the two clinical conditions, as reported by Wang and colleagues, “whether COVID-19 might trigger new-onset Alzheimer’s disease or accelerate its emergence is unclear” ( 82 ).…”