Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia

Wu, Min; Liao, Maolin; Huang, Rongfeng; Chen, Chunxiu; Tian, Tian; Wang, Hongying; Li, Jiayu; Li, Jibin; Sun, Yuxiang; Wu, Chaodong; Li, Qifu; Xiao, Xiaoqiu

doi:10.1016/j.gendis.2020.05.005

Cited by 39 publications

(35 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TREM2 is thought to be an essential molecule that regulates microglial phenotype and activation status. We found that M1 and M2 microglia increased in the spinal cord of PDN mice, and the increase of spinal microglial number was largely M1 microglia [51]. This nding is partly consistent with a recent study [51], which also observed a rise in M1 and M2 microglia in T2DM mice.…”

Section: Discussionsupporting

confidence: 92%

“…On the other hand, some studies reported an opposite deleterious effect of microglial TREM2 by facilitating neuroin ammation. Another research also recently associated TREM2 with diabetic brain disorder by showing that overexpression of TREM2 alleviated neuroin ammatory response and cognitive decline in Type 2 diabetes mellitus mice [51]. These results led us to clarify the role of TREM2 in PDN.…”

Section: Discussionmentioning

confidence: 85%

See 1 more Smart Citation

Contribution of Trem2 Signaling to the Development of Painful Diabetic Neuropathy by Mediating Microglial Polarization in Mice

Chen

Yue

et al. 2021

Preprint

View full text Add to dashboard Cite

Background Painful diabetic neuropathy (PDN) is a common and intractable complication of diabetes mellitus, with little effective treatment. PDN has been associated with spinal neuroinflammation characterized by microglial activation. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2), specifically localized on microglia, has been identified as a vital factor in modulating neuroinflammation and microglial phenotypes in neural diseases. Therefore, we hypothesized that spinal TREM2 might contribute to PDN and neuroinflammation by regulating microglial activity and phenotypes. Methods Type I diabetes mellitus was elicited by a single intraperitoneal administration of streptozotocin (STZ) in mice. The pain behaviors were reflected by paw mechanical withdrawal thresholds (PMWT) and thermal withdrawal latency (PTWL). Results We demonstrated that up-regulation of microglial TREM2 and amplification of both microglial M1 and M2 response was along with the presence of diabetes-related mechanical allodynia and thermal hypersensitivity. Moreover, we found that overexpression of TREM2 in microglia aggravated the symptom of PDN, amplified microglia M1 response, and suppressed microglia M2 polarization in the lumbar spinal cord of diabetic mice. However, inhibition of TREM2 with anti-TREM2 neutralizing antibodies attenuated mechanical allodynia and thermal hyperalgesia in diabetic mice. Besides, we identified Galectin-3 (GLT-3) as the potential ligand of the TREM2 receptor in facilitating the progression of PDN. Conclusions TREM2 could be a critical microglial membrane molecule that modulates microglial phenotypes pain hypersensitivity in PDN. GLT-3 might act as a specific ligand to trigger TREM2 signaling in PDN or other neuropathic pain.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 85%

Contribution of Trem2 Signaling to the Development of Painful Diabetic Neuropathy by Mediating Microglial Polarization in Mice

Chen

Yue

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Reduced phosphorylation of IRS leads to a decrease in the activation of PI3K and Akt, causing an increase in Tau-phosphorylation and the expression of Bax (pro-apoptotic protein) and a decrease in the expression of Bcl-2 (anti-apoptotic protein), resulting in neurodegeneration [ 14 , 15 ]. Prolonged consumption of HFD also increases the expression of TREM2 (primarily present in microglia) along mRNAs of IL-1β, TNF-α, TLR-4, iNOS and phosphorylation of p65 and Ilkβ in the C57BL/6J mice hippocampus [ 16 , 17 ], suggesting the crucial role of microglia in HFD-induced neuroinflammation. Apart from these findings, HFD also causes the cognitive decline through impaired hippocampal neurogenesis demonstrated through a reduced expression of BDNF and increased lipid peroxidation [ 57 ] and a reduction in the number of proliferating cells (Ki67+) and neuroblasts/immature neurons (DCX+) in the hippocampus [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Reduced activation of insulin causes a decrease in the activities of phosphoinositide 3-kinase (PI3K), and Akt, consequently increasing the Tau phosphorylation and the expression of pro-apoptotic protein and decreasing the expression of anti-apoptotic proteins, contributing to neurodegeneration in the hippocampus [ 14 , 15 ]. HFD also causes neuroinflammation in the hippocampus via a microglia-mediated pathway [ 16 , 17 ]. HFD impairs the learning ability (acquisition trial), and retrieval of long-term memory (probe trial conducted the day after the last acquisition trial) of rodents in the Morris water maze [ 16 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…HFD also causes neuroinflammation in the hippocampus via a microglia-mediated pathway [ 16 , 17 ]. HFD impairs the learning ability (acquisition trial), and retrieval of long-term memory (probe trial conducted the day after the last acquisition trial) of rodents in the Morris water maze [ 16 , 18 , 19 ]. The reports on HFD effects on short-term memory have rather yielded mixed results [ 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Abelmoschus Esculentus (L.) Moench’s Peel Powder Improves High-Fat-Diet-Induced Cognitive Impairment in C57BL/6J Mice

Prom-in

Kaewsrichan

Wangpradit

et al. 2020

IJERPH

View full text Add to dashboard Cite

Okra peel exhibits numerous therapeutic effects. This study explores the potential ameliorative effects of okra peel powder on high-fat-diet (HFD)-induced hypercholesterolemia and cognitive deficits. Thirty-six C57BL/6J male mice were randomly divided into six groups (n = 6 per group): (i) control, mice fed with a normal diet; (ii) HFD, mice fed with HFD; (iii) HFD-SIM, mice fed with HFD and given simvastatin (20 mg/kg/day); (iv) HFD-OP1; (v) HFD-OP2; (vi) HFD-OP3, mice fed with HFD and okra peel (200, 400, or 800 mg/kg/day, respectively). Following 10 weeks of treatments, the mice were subjected to the Morris water maze (MWM). Parameters such as weekly average body weight, food intake, and blood lipid profiles were also recorded. The HFD group showed a profound increase in total cholesterol and low-density lipoprotein concentration compared to the control group. All okra-treated and HFD-SIM groups performed better than the HFD group during acquisition trials, whereas only the HFD-OP1 produced a significantly higher number of entries into the platform zone during the probe trial. In sum, all three okra doses improved the learning ability of the mice. However, only the lowest dose of okra significantly improved the spatial reference memory retention.

show abstract

Boosting Microglial Lipid Metabolism via TREM2 Signaling by Biomimetic Nanoparticles to Attenuate the Sevoflurane‐Induced Developmental Neurotoxicity

Li,

Meng,

Peng

et al. 2023

Advanced Science

View full text Add to dashboard Cite

Lipid metabolism has been considered as a potential therapeutic target in sevoflurane‐induced neurotoxicity that can potentially affect the learning and memory function in the developmental brain. Recently, triggering receptor expressed on myeloid cells 2 (TREM2) is identified as a crucial step in regulating lipid metabolism and associated with the pathogenesis of neurodegenerative diseases. Herein, it is reported that quercetin modified Cu2‐xSe (abbreviated as CSPQ) nanoparticles can ameliorate sevoflurane‐induced neurotoxicity by tuning the microglial lipid metabolism and promoting microglial M2‐like polarization via TREM2 signaling pathway, in which the apolipoprotein E (ApoE), and adenosine triphosphate‐binding cassette transporters (ABCA1 and ABCG1) levels are upregulated. Furthermore, the protective effects of CSPQ nanoparticles against sevoflurane‐induced neurotoxicity via TREM2 are further demonstrated by the small interfering RNA (siRNA)‐TREM2 transfected BV2 cells, which are obviously not influenced by CSPQ nanoparticles. The cell membrane coated CSPQ (referred as CSPQ@CM) nanoparticles can significantly reduce sevoflurane‐induced learning and memory deficits, improve lipid metabolism dysfunction, and promote the remyelination in the hippocampus of mice. The study shows great potential of targeting microglial lipid metabolism in promoting remyelination of neurons for treatment of neurotoxicity and neurodegenerative diseases.

show abstract

Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia

Cited by 39 publications

References 47 publications

Contribution of Trem2 Signaling to the Development of Painful Diabetic Neuropathy by Mediating Microglial Polarization in Mice

Contribution of Trem2 Signaling to the Development of Painful Diabetic Neuropathy by Mediating Microglial Polarization in Mice

Abelmoschus Esculentus (L.) Moench’s Peel Powder Improves High-Fat-Diet-Induced Cognitive Impairment in C57BL/6J Mice

Boosting Microglial Lipid Metabolism via TREM2 Signaling by Biomimetic Nanoparticles to Attenuate the Sevoflurane‐Induced Developmental Neurotoxicity

Contact Info

Product

Resources

About