ArticleAging cell2022
Receptor for advanced glycation end products aggravates cognitive deficits in type 2 diabetes through binding of C-terminal AAs 2-5 to mitogen-activated protein kinase kinase 3 (MKK3) and facilitation of MEKK3-MKK3-p38 module assembly.
Article in Aging cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 22 citations in OpenAlex.
- Association of stress hyperglycemia ratio with the incidence of delirium in critically ill patients: a retrospective cohort study with exploratory machine-learning analyses.BMC neurology · 2026Article
- Targeting the RAGE-RIPK1 binding site attenuates diabetes-associated cognitive deficits.Journal of neuroinflammation · 2025Article
- Cognitive decline in older adults with type 2 diabetes: Unraveling site-specific glycoproteomic alterations.PloS one · 2025Article
- PRDX1 Interfering Peptide Disrupts Amino Acids 70-90 of PRDX1 to Inhibit the TLR4/NF-κB Signaling Pathway and Attenuate Neuroinflammation and Ischemic Brain Injury.Molecular neurobiology · 2024Article
- GLT-1 downregulation in hippocampal astrocytes induced by type 2 diabetes contributes to postoperative cognitive dysfunction in adult mice.CNS neuroscience & therapeutics · 2024Article
- Binding of RAGE and RIPK1 induces cognitive deficits in chronic hyperglycemia-derived neuroinflammation.CNS neuroscience & therapeutics · 2024Article
- Network pharmacology to unveil the mechanism of suanzaoren decoction in the treatment of alzheimer's with diabetes.Hereditas · 2024Article
- Flavonols as a Potential Pharmacological Intervention for Alleviating Cognitive Decline in Diabetes: Evidence from Preclinical Studies.Life (Basel, Switzerland) · 2023Review
- Advanced polymer hydrogels that promote diabetic ulcer healing: mechanisms, classifications, and medical applications.Biomaterials research · 2023Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
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Abstract
In this study, we explored the precise mechanisms underlying the receptor for advanced glycation end products (RAGE)-mediated neuronal loss and behavioral dysfunction induced by hyperglycemia. We used immunoprecipitation (IP) and GST pull-down assays to assess the interaction between RAGE and mitogen-activated protein kinase kinase 3 (MKK3). Then, we investigated the effect of specific mutation of RAGE on plasticity at hippocampal synapses and behavioral deficits in db/db mice through electrophysiological recordings, morphological assays, and behavioral tests. We discovered that RAGE binds MKK3 and that this binding is required for assembly of the MEKK3-MKK3-p38 signaling module. Mechanistically, we found that activation of p38 mitogen-activated protein kinase (MAPK)/NF-κB signaling depends on mediation of the RAGE-MKK3 interaction by C-terminal RAGE (ctRAGE) amino acids (AAs) 2-5. We found that ctRAGE R2A-K3A-R4A-Q5A mutation suppressed neuronal damage, improved synaptic plasticity, and alleviated behavioral deficits in diabetic mice by disrupting the RAGE-MKK3 conjugation. High glucose induces direct binding of RAGE and MKK3 via ctRAGE AAs 2-5, which leads to assembly of the MEKK3-MKK3-p38 signaling module and subsequent activation of the p38MAPK/NF-κB pathway, and ultimately results in diabetic encephalopathy (DE).
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