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

Zhou, Xiaoyan; Ying, Changjiang; Hu, Bin; Zhang, Yusheng; Gan, Tian; Zhu, Yandong; Wang, Nan; Li, Anan; Song, Yuanjian

doi:10.1111/acel.13543

Cited by 15 publications

(33 citation statements)

References 74 publications

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“…This is supported by our study that mutation of RAGE AAs 362-367 prevents the interaction of RAGE with RIPK1 and blocking activation of RIPK1 and its downstream in ammation-related signaling pathway in db/db mice. This is an important complement to our previous ndings, which reported that the binding of RAGE to MKK3 is an essential event for activation of the p38MAPK signal pathway in neuron under high-glucose conditions [21]. In the present study, the results show that the interaction between RAGE and RIPK1 induces RIPK1 phosphorylation and NLRP3 in ammasome activation in microglia.…”

Section: Discussionsupporting

confidence: 88%

“…Given the crucial role of RAGE in hyperglycemia-induced neuroin ammation, we initially investigated the RAGE-interacting proteins in hippocampus of db/db mice through liquid chromatograph-mass spectrometer (LC-MS) analysis. We found that the abundance of proteins associated with the mitogenactivated protein kinase (MAPK) signaling pathway was signi cantly increased in db/db mice [21]. It was worth mentioning that the protein abundance of RIPK1, which can induce neurodegenerative diseases by enhancing the in ammatory response, was found to be signi cantly elevated in db/db mice (Fig.…”

Section: Restults Rage Interacts With Ripk1 and Enhances Its Phosphor...mentioning

confidence: 76%

“…A growing body of evidence, including our previous studies, has shown that RAGE is involved in the progression of cognitive impairment in diabetes [21]. Increased RAGE in the brains of T2DM patients with mild cognitive de cit suggests that RAGE is a potential contributor to cognitive decline in patients with diabetes [30].…”

Section: Discussionmentioning

confidence: 95%

“…This nding is consistent with the evidence that the intracellular portion of RAGE is the vital domain for activating downstream signaling and inducing a series of cellular processes through direct coupling with intracellular proteins. The proximal membrane motif of C-terminal RAGE has been reported to contain an unusual α-turn that mediates the binding of RAGE to signaling proteins, including extracellular signal regulated kinase (ERK), mitogen-activated protein kinase kinase 3 (MKK3), and mammalian diaphanous-related formin (mDia1) [21,23,33]. Evidence suggests that RIPK1 homologous dimerization-mediated its phosphorylation, and RIPK1 DD is essential for its dimerization and interaction with membrane receptor protein to form complex that lead to activation of cascade signaling pathways [34].…”

Section: Discussionmentioning

confidence: 99%

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Binding of RAGE (AAs 362-367) and RIPK1 induces cognitive deficit in chronic hyperglycemia-derived neuroinflammation

Zhou

Zhu

Gao

et al. 2022

Preprint

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Background Chronic hyperglycemia-induced inflammation of the hippocampus is an important cause of cognitive deficit in diabetic patients. The receptor for advanced glycation end products (RAGE), which is widely expressed in the hippocampus of the brain, and is a crucial factor of inflammation and cognitive deficits. However, the precise role of RAGE in neuroinflammation is not fully elucidated. In the present study, we aimed to reveal the underlying mechanism by which RAGE regulates neuroinflammation in the pathogenesis of diabetes-induced cognitive impairment. Methods We employed db/db mice as type 2 diabetic mouse models for investigating whether receptor-interacting serine/threonine protein kinase 1 (RIPK1), which expressed in microglia in the hippocampal region, is a key protein that interacts with RAGE. GST pull-down assay and AutoDock Vina were performed to specify the key structural domain in RAGE that binds to RIPK1. Sophisticated molecular technologies including western blot (WB), co-immunoprecipitation (Co-IP) and immunofuorescence (IF) were applied to detect levels of key protein molecules. Furthermore, cognitive deficit of mice was assessed with Morris water maze (MWM), new object recognition (NOR) and fear conditioning tests. Results RAGE binds directly to RIPK1 via its amino acid sequences (AAs) 362–367, thereby upregulating the phosphorylation level of RIPK1, which is accompanied by the activation of NLRP3 inflammasome in microglia and ultimately leads to cognitive impairment in db/db mice. RAGE AAs 362–367 was mutated to reverse neuroinflammation and improve cognitive function in the hippocampus, suggesting that RAGE AAs 362–367 is a key structural domain that binds directly to PIPK1, while implying that hyperglycemia-induced inflammation in hippocampus is dependent on direct binding of RAGE and RIPK1. Conclusions These findings indicate that direct interaction of RAGE and RIPK1 via AAs 362–367 is an important mechanism for enhanced neuroinflammation in the hyperglycemic environment and is a key node in the development of cognitive deficit in diabetes.

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Section: Discussionsupporting

confidence: 88%

Section: Restults Rage Interacts With Ripk1 and Enhances Its Phosphor...mentioning

confidence: 76%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Binding of RAGE (AAs 362-367) and RIPK1 induces cognitive deficit in chronic hyperglycemia-derived neuroinflammation

Zhou

Zhu

Gao

et al. 2022

Preprint

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show abstract

“…Given the crucial role of RAGE in hyperglycemia‐induced neuroinflammation, we investigated RAGE‐interacting proteins in the hippocampus of db/db mice through liquid chromatograph–mass spectrometry (LC–MS) analysis. We found a significant increase in the abundance of proteins associated with the mitogen‐activated protein kinase (MAPK) signaling pathway in db/db mice 25 . In particular, the abundance of RIPK1 protein, which can induce neurodegenerative disease by enhancing the inflammatory response, was significantly elevated in db/db mice (Figure 1A1,A2).…”

Section: Resultsmentioning

confidence: 89%

Binding of RAGE and RIPK1 induces cognitive deficits in chronic hyperglycemia‐derived neuroinflammation

Zhou,

Zhu,

Gao

et al. 2023

CNS Neurosci Ther

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AimsChronic hyperglycemia‐induced inflammation of the hippocampus is an important cause of cognitive deficits in diabetic patients. The receptor for advanced glycation end products (RAGE), which is widely expressed in the hippocampus, is a crucial factor in this inflammation and the associated cognitive deficits. We aimed to reveal the underlying mechanism by which RAGE regulates neuroinflammation in the pathogenesis of diabetes‐induced cognitive impairment.MethodsWe used db/db mice as a model for type 2 diabetes to investigate whether receptor‐interacting serine/threonine protein kinase 1 (RIPK1), which is expressed in microglia in the hippocampal region, is a key protein partner for RAGE. GST pull‐down assays and AutoDock Vina simulations were performed to identify the key structural domain in RAGE that binds to RIPK1. Western blotting, co‐immunoprecipitation (Co‐IP), and immunofluorescence (IF) were used to detect the levels of key proteins or interaction between RAGE and RIPK1. Cognitive deficits in the mice were assessed with the Morris water maze (MWM) and new object recognition (NOR) and fear‐conditioning tests.ResultsRAGE binds directly to RIPK1 via the amino acid sequence (AAs) 362–367, thereby upregulating phosphorylation of RIPK1, which results in activation of the NLRP3 inflammasome in microglia and ultimately leads to cognitive impairments in db/db mice. We mutated RAGE AAs 362–367 to reverse neuroinflammation in the hippocampus and improve cognitive function, suggesting that RAGE AAs 362–367 is a key structural domain that binds directly to RIPK1. These results also indicate that hyperglycemia‐induced inflammation in the hippocampus is dependent on direct binding of RAGE and RIPK1.ConclusionDirect interaction of RAGE and RIPK1 via AAs 362–367 is an important mechanism for enhanced neuroinflammation in the hyperglycemic environment and is a key node in the development of cognitive deficits in diabetes.

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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

Ma,

Qi,

et al. 2024

Mol Neurobiol

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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

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 15 publications

References 74 publications

Binding of RAGE (AAs 362-367) and RIPK1 induces cognitive deficit in chronic hyperglycemia-derived neuroinflammation

Binding of RAGE (AAs 362-367) and RIPK1 induces cognitive deficit in chronic hyperglycemia-derived neuroinflammation

Binding of RAGE and RIPK1 induces cognitive deficits in chronic hyperglycemia‐derived neuroinflammation

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

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