TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer&amp;#x2019;s disease mice

Wang, Yaping; Yc, Lin; Wang, Linhan; Zhan, Hongrui; Luo, Xiaoting; Zeng, Yanyan; Wu, Wen; Zhang, Xingmei; Wang, Fang

doi:10.18632/aging.104104

Cited by 108 publications

(56 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The PI3K/AKT pathway is the most commonly signaling pathway in pulmonary diseases, including pulmonary fibrosis ( Hsu et al, 2017 ; Wang et al, 2018 ; Shi et al, 2019 ; Wan et al, 2019 ). Several studies have suggested that the PI3K/AKT signaling pathway is particularly important in mediating ER stress in various diseases ( Hsu et al, 2017 ; Song et al, 2019b ; Wang et al, 2020 ). However, the mechanisms of the PI3K/AKT signaling pathway underlying the effect of eHSP90α on pulmonary fibrosis remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis

et al. 2021

View full text Add to dashboard Cite

Pulmonary fibrosis is characterized by alveolar epithelial cell injury, lung fibroblast proliferation, differentiation, and extracellular matrix (ECM) deposition. Our previous study indicated that extracellular HSP90α (eHSP90α) promotes pulmonary fibrosis by activating the MAPK signaling pathway. Thus, treatment with 1G6-D7 (a selective HSP90α monoclonal antibody) to antagonize eHSP90α could effectively ameliorate fibrosis. This study aimed to elucidate the mechanism underlying the effects of eHSP90α in pulmonary fibrosis by focusing on its link with endoplasmic reticulum (ER) stress. Our results showed that eHSP90α promoted lung fibroblast differentiation by activating ER stress. Treatment with the ER stress inhibitor tauroursodeoxycholate (TUDCA) or glucose-regulated protein 78 kDa (GRP78) depletion significantly abrogated the effect of eHSP90α on ER stress and fibroblast activation. In addition, eHSP90α induced ER stress in fibroblasts via the phosphoinositide-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which could be blocked by the PI3K/AKT inhibitor LY294002, and blockade of eHSP90α by 1G6-D7 markedly inhibited ER stress in the model, indicating preventive and therapeutic applications. Intriguingly, we observed that TUDCA effectively reduced the secretion of eHSP90α in vitro and in vivo. In conclusion, this study shows that the interaction between eHSP90α and ER stress plays a crucial role in pulmonary fibrosis, indicating a positive feedback in lung fibroblasts. Targeting eHSP90α and alleviating fibroblast ER stress may be promising therapeutic approaches for pulmonary fibrosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The calcium concentration also triggers calmodulin–calcium interaction, which modulates synaptic plasticity, learning, and memory ( Supplementary Table S3 ) [ 25 ]. In addition, triggering receptor expressed on myeloid cells 2 ( TREM2 ) gene has been shown to protect neurons from inflammation and to ameliorate memory impairment in AD mice through interacting with the AKT gene in the PI3K/AKT/FoxO3a signaling pathway [ 26 ]. Moreover, blockage of tropomyosin-related kinase (Trk) receptors type B of the BDNF gene from δ-secretase cleavage may prevent production of β -amyloid [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Genetic Variants behind Cardiovascular Diseases and Dementia

Chen

2020

Genes

View full text Add to dashboard Cite

Cardiovascular diseases (CVDs) and dementia are the leading causes of disability and mortality. Genetic connections between cardiovascular risk factors and dementia have not been elucidated. We conducted a scoping review and pathway analysis to reveal the genetic associations underlying both CVDs and dementia. In the PubMed database, literature was searched using keywords associated with diabetes mellitus, hypertension, dyslipidemia, white matter hyperintensities, cerebral microbleeds, and covert infarctions. Gene lists were extracted from these publications to identify shared genes and pathways for each group. This included high penetrance genes and single nucleotide polymorphisms (SNPs) identified through genome wide association studies. Most risk SNPs to both diabetes and dementia participate in the phospholipase C enzyme system and the downstream nositol 1,4,5-trisphosphate and diacylglycerol activities. Interestingly, AP-2 (TFAP2) transcription factor family and metabolism of vitamins and cofactors were associated with genetic variants that were shared by white matter hyperintensities and dementia, and by microbleeds and dementia. Variants shared by covert infarctions and dementia were related to VEGF ligand–receptor interactions and anti-inflammatory cytokine pathways. Our review sheds light on future investigations into the causative relationships behind CVDs and dementia, and can be a paradigm of the identification of dementia treatments.

show abstract

“…TREM2 loss confers resilience to synaptic and cognitive impairment in aged mice [26]. TREM2 also ameliorates neuroin ammatory responses and cognitive impairment via the PI3K/AKT/FoxO3a pathway in AD mice [27].…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Pretreatment Adipose-derived Stem Cell Exosomes Improve Cognition by Delivery Circ-Epc1 and Shifting Microglial M1/M2 Polarization in Alzheimer’s Disease Mice Model

Liu

Jin

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Alzheimer’s disease (AD) is the most major dementia in the globe. Increasing evidence informs that exosomes from hypoxic pretreatment adipose-derived stem cells (ADSCs) could therapeutically affect cognitive function in AD-associated pathophysiology. However, their role and regulatory mechanism remain largely unknown. Methods: High-throughput sequencing was used to identify differentially expressed exosomal circRNAs from ADSCs or hypoxia pretreated ADSCs. Luciferase reporter assays and RT-qPCR were used to investigate the relationships between circ-Epc1, miR-770-3p, and TREM2. APP/PS1 double transgenic AD model mice were then utilized to study therapeutic effect regarding circ-Epc1 in ADSCs exosomes. BV2 cells were used to understand the regulatory relationship between circ-Epc1, miR-770-3p, and TREM2 and how these interactions modulated phenotypic transformation and inflammatory cytokine expression in microglia. Results: The result show that exosomes from hypoxia pretreatment ADSCs had a greater therapeutic effect at improving cognitive function by decreasing neuronal damage in the hippocampus. High-throughput sequencing found that circ-Epc1 played an important role in hypoxia pretreated ADSC exosomes regarding their ability to improve cognitive function. Luciferase reporter assays showed that TREM2 and miR-770-3p were downstream targets of circ-Epc1. Overexpressing miR-770-3p or downregulating TREM2 reversed the effects of circ-Epc1 on M2 microglia under LPS treatment. In vivo experiments showed that circ-Epc1-containing ADSC exosomes increased the therapeutic effect of exosome at improving cognitive function by decreasing neuronal damage and shifting hippocampal microglia from M1 to M2 polarization. Conclusions: Taken together, the data found that hypoxic pretreatment ADSCs exosomes improve cognition by delivery circ-Epc1 and shifting microglial M1/M2 polarization in alzheimer’s disease mice model.

show abstract

TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice

Cited by 108 publications

References 44 publications

Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis

Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis

Genetic Variants behind Cardiovascular Diseases and Dementia

Hypoxic Pretreatment Adipose-derived Stem Cell Exosomes Improve Cognition by Delivery Circ-Epc1 and Shifting Microglial M1/M2 Polarization in Alzheimer’s Disease Mice Model

Contact Info

Product

Resources

About