Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment

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-Tau) 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, ϵ-[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-Tau 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-Tau 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.

Integration Analysis of m6A-SNPs and eQTLs Associated With Sepsis Reveals Platelet Degranulation and Staphylococcus aureus Infection are Mediated by m6A mRNA Methylation

“…HSPA1B, with 61 m 6 A-cis-eQTLs, also named HSP70, is involved in the inflammatory response, which is an important biological step in the development of sepsis (Table S2). Research on different phases of sepsis found that HSPA1B can be considered a serum marker for the acute proinflammatory phase (Gasparotto et al, 2018). Study on Multiple organ dysfunction syndrome in sepsis found that increased HSPA1B has an anti-inflammatory effect (Wang et al, 2016).…”

Physiological and pathogenic role of scavenger receptors in humans

“…Возможно и острое развитие нейродегенерации. Так, в восстановительный период экспериментального сепсиса у крыс фиксируется в гиппокампе гибель нейронов, отложение таупротеина и β-амилоида, а также развитие когнитивных расстройств [67]. При этом блокада SR-J1 (RAGE) антителами существенно снижала проявления нейродегенерации, а накоплению в мозге лигандов SR-J1, наоборот, способствовала.…”

“…В свою очередь, SR-J1 (RAGE) способствует патологической активации эндотелия сосудов и других клеток в качестве неблагоприятного фактора развития сепсиса и других критических состояний [128,186]. Кроме того, SR-J1 может способствовать вторичному развитию нейродегенерации в восстановительный период сепсиса, реагируя на образование амилоидных белков в головном мозге [67]. Также в экспериментальных моделях сепсиса доказана негативная роль для выживания животных и развития микроциркуляторных расстройств SR-E1 (LOX-1) и их лиганда -oxLDL [8].…”

The Receptor for Advanced Glycation Endproducts (RAGE) and Mediation of Inflammatory Neurodegeneration

“…However, in the late and progressive stages of AD dysfunction, depletion of the enzyme's chief and essential cofactor, glutathione, reduces overall activity of the GLO1-AGE detoxifying system, thus facilitating increased AGE production and accumulation [65,66]. Altogether, these findings underscore a potentially profound link between peripheral and central inflammation, which prompts the question: to what extent might anti-AGE/RAGE therapies provide protective measures for neurodegeneration and AD, given the prominence of cellular stress driven by increased RAGE ligand burden [67][68][69].…”