Long COVID as a Tauopathy: Of “Brain Fog” and “Fusogen Storms”

Abstract

Long COVID, also called post-acute sequelae of SARS-CoV-2, is characterized by a multitude of lingering symptoms, including impaired cognition, that can last for many months. This symptom, often called “brain fog”, affects the life quality of numerous individuals, increasing medical complications as well as healthcare expenditures. The etiopathogenesis of SARS-CoV-2-induced cognitive deficit is unclear, but the most likely cause is chronic inflammation maintained by a viral remnant thriving in select body reservoirs. These viral sanctuaries are likely comprised of fused, senescent cells, including microglia and astrocytes, that the pathogen can convert into neurotoxic phenotypes. Moreover, as the enteric nervous system contains neurons and glia, the virus likely lingers in the gastrointestinal tract as well, accounting for the intestinal symptoms of long COVID. Fusogens are proteins that can overcome the repulsive forces between cell membranes, allowing the virus to coalesce with host cells and enter the cytoplasm. In the intracellular compartment, the pathogen hijacks the actin cytoskeleton, fusing host cells with each other and engendering pathological syncytia. Cell–cell fusion enables the virus to infect the healthy neighboring cells. We surmise that syncytia formation drives cognitive impairment by facilitating the “seeding” of hyperphosphorylated Tau, documented in COVID-19. In our previous work, we hypothesized that the SARS-CoV-2 virus induces premature endothelial senescence, increasing the permeability of the intestinal and blood–brain barrier. This enables the migration of gastrointestinal tract microbes and/or their components into the host circulation, eventually reaching the brain where they may induce cognitive dysfunction. For example, translocated lipopolysaccharides or microbial DNA can induce Tau hyperphosphorylation, likely accounting for memory problems. In this perspective article, we examine the pathogenetic mechanisms and potential biomarkers of long COVID, including microbial cell-free DNA, interleukin 22, and phosphorylated Tau, as well as the beneficial effect of transcutaneous vagal nerve stimulation.

Evaluating p-tau217 and p-tau231 as Biomarkers for Early Diagnosis and Differentiation of Alzheimer’s Disease: A Narrative Review

“…This emphasizes the distinct and critical role of p-tau in the aftermath of TBI and its potential as a prognostic marker for long-term recovery and the development of tauopathies. The review by Sfera [124] explores the role of tau and p-tau blood levels in cognitive impairments among individuals with long COVID-19, also referred to as the post-acute sequelae of SARS-CoV-2. The authors suggest that chronic inflammation, triggered by viral remnants in specific body sites, results in the formation of pathological syncytia involving microglia and astrocytes.…”

SARS-CoV-2 and Brain Health: New Challenges in the Era of the Pandemic

“…The immune cells that have been activated can eliminate the virus by releasing cytokines such as interferon (IFN), interleukin (IL), tumor necrosis factor (TNF), and chemokines [84][85][86][87][88]. Under typical biological conditions, it is observed that pro-inflammatory factors and immune cells can establish a positive feedback cycle, thereby contributing to the maintenance of cytokine balance [84,89]. However, it is essential to note that infection with SARS-CoV-2 has been observed to elicit an exaggerated immune response in specific individuals.…”