Abstract
Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-β peptide (Aβ) and Ser-202-phosphorylated Tau (p-TauSer-202) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1β, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, Nϵ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aβ and p-TauSer-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aβ and p-TauSer-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation.
Highlights
Patients recovering from sepsis have higher rates of central nervous system (CNS) morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases
We investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery
Overall these data suggest that RAGE signaling in the CNS exerts an important role in the progressive impairment of brain function that arises after the recovery from the acute phase of sepsis, and it may be involved in the long-term development of brain dysfunction and neurodegeneration triggered by episodes of acute systemic inflammation, including polymicrobial sepsis
Summary
The results presented here indicate the following: (i) RAGE signaling increases as acute pro-inflammatory markers decrease over the 30 days following CLP, in serum, and CNS; and (ii) blocking of RAGE in the hippocampus inhibits neuroinflammatory and neurodegenerative markers in this brain region, as well as cognitive deficits that are observed 30 days after CLP Overall these data suggest that RAGE signaling in the CNS exerts an important role in the progressive impairment of brain function that arises after the recovery from the acute phase of sepsis, and it may be involved in the long-term development of brain dysfunction and neurodegeneration triggered by episodes of acute systemic inflammation, including polymicrobial sepsis
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