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Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment.
J Biol Chem. 2018 01 05; 293(1):226-244.JB

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.

Authors+Show Affiliations

From the Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003 RS, Brazil.From the Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003 RS, Brazil.From the Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003 RS, Brazil.From the Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003 RS, Brazil.From the Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003 RS, Brazil.the Laboratório de Fisiopatologia Experimental, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, and.the Laboratório de Fisiopatologia Experimental, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, and.the Laboratório de Fisiopatologia Experimental, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, and.Laboratório de Neurociências at Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense-Criciúma, Criciúma 88806-000 SC, Brazil, and. the Translational Psychiatry Program and. Center of Excellence on Mood Disorders at Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston and. Neuroscience Graduate Program, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030.Laboratório de Neurociências at Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense-Criciúma, Criciúma 88806-000 SC, Brazil, and. the Translational Psychiatry Program and. Center of Excellence on Mood Disorders at Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston and. Neuroscience Graduate Program, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030.Laboratório de Neurociências at Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense-Criciúma, Criciúma 88806-000 SC, Brazil, and. the Translational Psychiatry Program and. Center of Excellence on Mood Disorders at Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston and. Neuroscience Graduate Program, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030.the Laboratório de Fisiopatologia Experimental, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, and.From the Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003 RS, Brazil, daniel.gelain@ufrgs.br.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29127203

Citation

Gasparotto, Juciano, et al. "Receptor for Advanced Glycation End Products Mediates Sepsis-triggered Amyloid-β Accumulation, Tau Phosphorylation, and Cognitive Impairment." The Journal of Biological Chemistry, vol. 293, no. 1, 2018, pp. 226-244.
Gasparotto J, Girardi CS, Somensi N, et al. Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment. J Biol Chem. 2018;293(1):226-244.
Gasparotto, J., Girardi, C. S., Somensi, N., Ribeiro, C. T., Moreira, J. C. F., Michels, M., Sonai, B., Rocha, M., Steckert, A. V., Barichello, T., Quevedo, J., Dal-Pizzol, F., & Gelain, D. P. (2018). Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment. The Journal of Biological Chemistry, 293(1), 226-244. https://doi.org/10.1074/jbc.M117.786756
Gasparotto J, et al. Receptor for Advanced Glycation End Products Mediates Sepsis-triggered Amyloid-β Accumulation, Tau Phosphorylation, and Cognitive Impairment. J Biol Chem. 2018 01 5;293(1):226-244. PubMed PMID: 29127203.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment. AU - Gasparotto,Juciano, AU - Girardi,Carolina S, AU - Somensi,Nauana, AU - Ribeiro,Camila T, AU - Moreira,José C F, AU - Michels,Monique, AU - Sonai,Beatriz, AU - Rocha,Mariane, AU - Steckert,Amanda V, AU - Barichello,Tatiana, AU - Quevedo,João, AU - Dal-Pizzol,Felipe, AU - Gelain,Daniel P, Y1 - 2017/11/10/ PY - 2017/03/16/received PY - 2017/11/09/revised PY - 2017/11/12/pubmed PY - 2018/11/28/medline PY - 2017/11/12/entrez KW - Tau protein (Tau) KW - amyloid-β (Aβ) KW - neurodegeneration KW - neuroinflammation KW - receptor for advanced glycation end products (RAGE) KW - sepsis SP - 226 EP - 244 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 293 IS - 1 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/29127203/Receptor_for_advanced_glycation_end_products_mediates_sepsis_triggered_amyloid_β_accumulation_Tau_phosphorylation_and_cognitive_impairment_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=29127203 DB - PRIME DP - Unbound Medicine ER -