Extracellular vesicles from hyperammonemic rats induce neuroinflammation in hippocampus and impair cognition in control rats

Patients with liver cirrhosis show hyperammonemia and peripheral inflammation and may show hepatic encephalopathy with cognitive impairment, reproduced by rats with chronic hyperammonemia. Peripheral inflammation induces neuroinflammation in hippocampus of hyperammonemic rats, altering neurotransmission and leading to cognitive impairment. Extracellular vesicles (EVs) may transmit pathological effects from the periphery to the brain. We hypothesized that EVs from peripheral blood would contribute to cognitive alterations in hyperammonemic rats. The aims were to assess whether EVs from plasma of hyperammonemic rats (HA-EVs) induce cognitive impairment and to identify the underlying mechanisms. Injection of HA-EVs impaired learning and memory, induced microglia and astrocytes activation and increased TNF alpha and IL-1 beta. Ex vivo incubation of hippocampal slices from control rats with HA-EVs reproduced these alterations. HA-EVs increased membrane expression of TNFR1, reduced membrane expression of TGF beta R2 and Smad7 and I kappa B alpha levels and increased I kappa B alpha phosphorylation. This led to increased activation of NF-kappa B and IL-1 beta production, altering membrane expression of NR2B, GluA1 and GluA2 subunits, which would be responsible for cognitive impairment. All these effects of HA-EVs were prevented by blocking TNF alpha, indicating that they were mediated by enhanced activation of TNFR1 by TNF alpha. We show that these mechanisms are very different from those leading to motor incoordination, which is due to altered GABAergic neurotransmission in cerebellum. This demonstrates that peripheral EVs play a key role in the transmission of peripheral alterations to the brain in hyperammonemia and hepatic encephalopathy, inducing neuroinflammation and altering neurotransmission in hippocampus, which in turn is responsible for the cognitive deficits.

Automated summary

Patients with liver cirrhosis may experience cognitive impairment due to hyperammonemia and peripheral inflammation, which can also be replicated in rats with chronic hyperammonemia. Neuroinflammation in the hippocampus, caused by peripheral inflammation, alters neurotransmission and leads to cognitive impairment. Extracellular vesicles (EVs) from peripheral blood are believed to play a role in transmitting these peripheral alterations to the brain.