Sepsis-associated brain injury: underlying mechanisms and potential therapeutic strategies for acute and long-term cognitive impairments

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis causes cerebral dysfunction in the short and long term and induces disruption of the blood-brain barrier (BBB), neuroinflammation, hypoperfusion, and accumulation of amyloid β (Aβ) and tau protein in the brain. White matter changes and brain atrophy can be detected using brain imaging, but unfortunately, there is no specific treatment that directly addresses the underlying mechanisms of cognitive impairments in sepsis. Here, we review the underlying mechanisms of sepsis-associated brain injury, with a focus on BBB dysfunction and Aβ and tau protein accumulation in the brain. We also describe the neurological manifestations and imaging findings of sepsis-associated brain injury, and finally, we propose potential therapeutic strategies for acute and long-term cognitive impairments associated with sepsis. In the acute phase of sepsis, we suggest using antibiotics (such as rifampicin), targeting proinflammatory cytokines, and preventing ischemic injuries and hypoperfusion. In the late phase of sepsis, we suggest targeting neuroinflammation, BBB dysfunction, Aβ and tau protein phosphorylation, glycogen synthase kinase-3 beta (GSK3β), and the receptor for advanced glycation end products (RAGE). These proposed strategies are meant to bring new mechanism-based directions for future basic and clinical research aimed at preventing or ameliorating acute and long-term cognitive impairments in patients with sepsis.

Keywords: Alzheimer’s disease; Amyloid-beta; Cognitive impairment; Neuroinflammation; Sepsis; Tau protein; White matter change.

Fig. 1

Schematic representation of underlying mechanisms of sepsis-related brain injuries. Inflammation caused by sepsis affects a wide range of processes. In the short term, it induces dysfunction of endothelial cells (EC) leading to blood–brain barrier (BBB) leakage. Proinflammatory cytokines can lead to BBB leakage and contribute to hypoperfusion. Hypoperfusion and dysfunction of coagulation induce ischemia/hypoxia and microhemorrhage. These factors ultimately lead to changes in the white matter in the brain. Sepsis-related inflammation may have a long-term effect. Sepsis may lead to amyloid β (Aβ) and tau protein in the brain. Ultimately, these processes lead to cognitive impairment