Filipe Menezes ¹ Julys Da Fonseca Palmeira ² Juliana dos Santos Oliveira ² Bergmann Morais Ribeiro ² Otávio Toledo Nóbrega ² Gustavo Adolfo Arganãraz ² Enrique Roberto Argañaraz ^2*

• ¹ Instituto de Pesquisas Energéticas e Nucleares (IPEN), São Paulo, São Paulo, Brazil
• ² University of Brasilia, Brasilia, Brazil

The persistence or emergence of long-term symptoms following resolution of primary SARS-CoV-2 infection is referred to as long COVID or post-acute sequelae of COVID-19 (PASC). PASC predominantly affects the cardiovascular, neurological, respiratory, gastrointestinal, reproductive, and immune systems. Among these, the central nervous system (CNS) is significantly impacted, leading to a spectrum of symptoms, including fatigue, headaches, brain fog, cognitive impairment, anosmia, hypogeusia, neuropsychiatric symptoms, and peripheral neuropathy (neuro-PASC). However, the risk factors and pathogenic mechanisms responsible for neuro-PASC remain unclear. This review hypothesis discusses the leading hypotheses regarding the pathophysiological mechanisms involved in long COVID/PASC, focusing on neuro-PASC. We propose vascular dysfunction mediated by activation of astrocytes and pericytes followed by blood-brain barrier (BBB) disruption as underlying pathophysiological mechanisms of neurological manifestations. Additionally, we provide insights into the role of spike protein at the blood-brain interface. Finally, we explore the potential pathogenic mechanisms initiated by the interaction between the spike protein and cellular receptors at the brain endothelial and tissue levels.