TREM-1 Aggravates Diabetic Associated Cognitive Impairment by Inducing Iron Deposition in Microglia via ERS

Abstract

AbstractBackgroundCognitive impairment is one of the serious complications in diabetic patients. Iron accumulation is thought to be related to degenerative diseases and diabetes. Microglia have been shown to have features of iron accumulation in Alzheimer 's disease (AD). Triggering receptor expressed on myeloid cells-1(TREM-1)acts as an activating receptor for myeloid cells and is elevated in several neurodegenerative diseases. It is unclear whether microglial iron overload is involved in diabetic associated cognitive impairment (DACI), and whether there is an association between TREM-1 and iron metabolism.MethodsWe established a model cultured in high glucose (HG) for 72 hours in BV2/HMC3 and another one high fat diet (HFD) combined with STZ in C57 mice. Intracellular mitochondrial changes were observed by Transmission Electron Microscopy, intracellular Fe2 +, GSH/GSSG, MDA and ROS were detected using kits to assess lipid peroxidation in microglia. Prussian blue staining was used to observe iron deposition in the hippocampus. Cognitive performance of mice was assessed by Y-maze and novel object experiments (NOR). Western blot and immunofluorescence were used to observe the expression of iron and antioxidant-related protein (FPN1, FTL, TFR1,GPX4), apoptosis-related protein (BCL-2, BAX and Caspase3), TREM-1, endoplasmic reticulum stress (ERS)-related protein (BIP, P-IRE, IRE, ATF6, P-PERK, PERK, P-eIF2α, eIF2α, ATF4, CHOP).ResultsWe found that hippocampus and microglia undergo iron overload and antioxidant inactivation in HFD/STZ mice. Iron overload, with increase of TREM-1 and antioxidant inactivation, occurred in BV2/HMC3 cultured by HG. Fer-1 could alleviate it by inhibiting HG-induced change of FPN1, GPX4, TFR1, as well as Fe2 +, GSH/GSSG ratio, MDA and ROS. Inhibiting TREM-1 by LP17 could block it, too. Furthermore, PERK/ eIF2α/ATF4/CHOP was obviously down-regulated by LP17 in HG cultured BV2. When LP17 was administered intraperitoneally, cognitive impairment was improved in HFD/STZ mice, iron deposition and antioxidant inactivation in microglia of hippocampus were relieved.ConclusionsIn this study, we found that iron deposition and antioxidant inactivation occurred in microglia of hippocampus in HFD/STZ mice, accompanied by increase of TREM-1, while inhibition of TREM-1 expression alleviated it and improved cognitive dysfunction, which was partially regulated by PERK/ eIF2α/ATF4/CHOP.