Hippocampal β2-microglobulin mediates sepsis-induced cognitive impairment

Abstract

Acute brain dysfunction is a frequent complication in sepsis patients and is associated with long-term neurocognitive consequences and increased mortality, yet the underlying mechanism remains unclear. Emerging evidence has suggested that β2-microglobulin [a component of major histocompatibility complex (MHC) class I molecules] is involved in cognitive dysfunction in various neurological diseases. Therefore, the present study tested the hypothesis that β2-microglobulin in the brain also mediates sepsis-induced cognitive impairment. In the present study, wild-type and antigen processing 1 (Tap1)-deficient mice (Tap1-/-) were subjected to cecal ligation and puncture (CLP). Survival rate, cognitive function, and biochemical analysis were performed at the indicated time points. The data revealed that CLP induced anxiety-like behavior and impaired hippocampal-dependent contextual memory in wild-type mice, which was accompanied by hippocampal microglial activation, increased level of interleukin-1β, and decreased concentrations of brain derived neurotrophic factor and postsynaptic density protein 95. Notably, it was demonstrated that Tap1-/- mice with reduced cell surface expression of MHCI protected mice from anxiety-like behavior and impaired hippocampal-dependent contextual memory and reversed most of these biochemical parameters following sepsis development. In summary, the results of the present study suggest that β2-microglobulin negatively regulates cognitive impairment in an animal model of sepsis induced by CLP.