HMGB1 gene silencing inhibits neuroinflammation via down-regulation of NF-κB signaling in primary hippocampal neurons induced by Aβ25-35.

Abstract

High mobility group box 1 protein (HMGB1) is potentially triggered by Aβ oligomers and other sterile injuries, and is a non-histone DNA binding nuclear protein with roles in neural development and neurodegeneration, which contribute to memory impairment and chronic neuroinflammation in the brain. However, the exact molecular mechanisms of HMGB1 activation in Alzheimer's disease (AD) were previously unknown. The present study aimed to elucidate the effects of HMGB1 in Aβ25-35-induced neuroinflammation in hippocampal neuron cultures. RNA interference (RNAi) HMGB1 treatment significantly reduced Aβ25-35-induced HMGB1 expression by almost 70% in primary hippocampal neurons. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay (ELISA) demonstrated that short hairpin RNA (shRNA) for HMGB1 ameliorated Aβ25-35-treated neuroinflammation, including activation of advanced glycosylation end product-specific receptor (RAGE), toll-like receptor 4 (TLR4), and nuclear factor-kappa B (NF-κB)-p65, as well as induced the release of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IL-6, and HMGB1 in primary hippocampal neurons and the culture supernatant. In addition, pretreatment with HMGB1-shRNA dramatically reduced both the degree of nuclear-cytoplasmic HMGB1 translocation of HMGB1 and NF-κB DNA binding. Together, the data indicate that HMGB1 mediates the pathogenesis of AD by activating RAGE/TLR4 signaling and that shRNA targeting HMGB1 may be a promising therapeutic strategy for treating AD.

• Authors: Ke Nan, Yuan Han, Qianjuan Fang, Chenmiao Huang, Liu Yu, Wenwei Ge, Fangfang Xiang, Yuan-Xiang Tao, Hong Cao, Jun Li
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 67 Pg. 294-301 (Feb 2019) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 30572254 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• HMGB1 Protein
• Hbp1 protein, rat
• NF-kappa B

Topics

• Amyloid beta-Peptides (pharmacology)
• Animals
• Cells, Cultured
• Down-Regulation (drug effects)
• Gene Silencing
• HMGB1 Protein (genetics, metabolism)
• Hippocampus (cytology)
• NF-kappa B (genetics, metabolism)
• Neurons (drug effects)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)