Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina, Av. Universitária, 1105 - Bairro Universitário, Criciúma, SC, CEP: 88806-000, Brazil.
Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
Mol Neurobiol. 2020 Feb;57(2):1159-1169. doi: 10.1007/s12035-019-01808-1. Epub 2019 Nov 7.
Inflammatory cytokines are related to impaired learning and memory processes in the central nervous system, contributing to the cognitive dysfunction present in sepsis survivors. In sepsis, brain of survivors presented increased deposition of amyloid-beta (Aβ) peptide and this was associated with cognitive impairment. However, it is not known if the upregulation of secretase pathway is involved the deposition of Aβ peptide and consequent development of cognitive impairment in survivors. The aim of the study is to evaluate the effects of secretase inhibitors on behavioral, Aβ accumulation, and neuroinflammatory parameters in rats submitted to sepsis. Sepsis was induced by cecal ligation and perforation in Wistar rats, and the activity of alpha-, beta-, and gamma-secretases was determined in the hippocampus and prefrontal at different times. Additionally, in a different cohort of animal's epigallocatechin gallate, a beta-secretase inhibitor or a gamma-secretase inhibitor was administrated once a day for three consecutive days. Fifteen or 30 days after sepsis induction, Aβ content, TNF-α, IL-1β, and IL-6 and cognitive performance were determined. There was no increase in alpha-secretase activity. Both beta- and gamma-secretase activities increased, mainly late after sepsis. The inhibition of beta- or gamma-secretases improved cognitive performance 10 days after sepsis induction, and beta-secretase inhibition improved cognitive performance up to 30 days after sepsis induction. Furthermore, beta-secretase inhibition decreased IL-1β and Aβ brain levels. It was demonstrated that during sepsis development there was an increase in the amyloidogenic route, and the inhibition of this pathway promoted attenuation of neuroinflammation, Aβ peptide content, and improvement of cognitive impairment.
炎症细胞因子与中枢神经系统学习和记忆过程受损有关，导致脓毒症幸存者出现认知功能障碍。在脓毒症中，幸存者的大脑中出现了淀粉样β（Aβ）肽的沉积增加，这与认知障碍有关。然而，目前尚不清楚是否上调分泌酶途径参与了 Aβ肽的沉积以及幸存者认知障碍的发展。本研究旨在评估分泌酶抑制剂对脓毒症大鼠行为、Aβ积累和神经炎症参数的影响。通过盲肠结扎穿孔术在 Wistar 大鼠中诱导脓毒症，并在不同时间测定海马体和前额叶中的α-、β-和γ-分泌酶的活性。此外，在另一组动物中，每天给予表没食子儿茶素没食子酸酯（一种β-分泌酶抑制剂）或γ-分泌酶抑制剂，连续 3 天。在脓毒症诱导后 15 或 30 天，测定 Aβ含量、TNF-α、IL-1β、IL-6 和认知表现。α-分泌酶活性没有增加。β-和γ-分泌酶活性均增加，主要在脓毒症后晚期增加。β-或γ-分泌酶抑制可改善脓毒症诱导后 10 天的认知表现，β-分泌酶抑制可改善脓毒症诱导后 30 天的认知表现。此外，β-分泌酶抑制可降低脑内 IL-1β 和 Aβ 水平。研究表明，在脓毒症发展过程中，淀粉样蛋白生成途径增加，抑制该途径可减轻神经炎症、Aβ肽含量并改善认知障碍。
