Regulation of Tau protein phosphorylation by glucosamine-induced O-GlcNAcylation as a neuroprotective mechanism in a brain ischemia-reperfusion model

Cardozo, Carlos Julio Márquez; Vera, Adrianna; Quintana-Peña, Valentina; Arango-Dávila, César Augusto; Rengifo, Juliana

doi:10.1080/00207454.2021.1901695

Cited by 7 publications

(4 citation statements)

References 36 publications

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“…GLN has already been shown to promote cognitive performance in mice, which is accompanied by induced BDNF expression and cAMP/PKA pathway activation in brain tissues [40]. In addition, the contribution of GLN to the alleviation of various brain pathologic scenarios has been previously shown-it potentially acts by suppressing inflammatory cascades in animal models of autoimmune encephalomyelitis [27] and ischemia [28,30] and reducing the phosphorylation of the Tau protein in a brain ischemia-reperfusion model [29]. Differently from these studies, our current findings identified a novel molecule FGF21 induced by GLN as the key molecule in the brain, presumably playing beneficial roles in learning and memory functions.…”

Section: Discussionmentioning

confidence: 99%

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Glucosamine Enhancement of Learning and Memory Functions by Promoting Fibroblast Growth Factor 21 Production

Chao,

Wu,

Yeh

et al. 2024

IJMS

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Fibroblast growth factor 21 (FGF21) plays a crucial role in metabolism and brain function. Glucosamine (GLN) has been recognized for its diverse beneficial effects. This study aimed to elucidate the modulation of FGF21 production by GLN and its impact on learning and memory functions. Using both in vivo and in vitro models, we investigated the effects of GLN on mice fed with a normal diet or high-fat diet and on mouse HT22 hippocampal cells, STHdhQ7/Q7 striatal cells, and rat primary cortical neurons challenged with GLN. Our results indicated that GLN promotes learning and memory functions in mice and upregulates FGF21 expression in the hippocampus, cortex, and striatum, as well as in HT22 cells, STHdhQ7/Q7 cells, and cortical neurons. In animals receiving GLN together with an FGF21 receptor FGFR1 inhibitor (PD173074), the GLN-enhanced learning and memory functions and induction of FGF21 production in the hippocampus were significantly attenuated. While exploring the underlying molecular mechanisms, the potential involvement of NF-κB, Akt, p38, JNK, PKA, and PPARα in HT22 and NF-κB, Akt, p38, and PPARα in STHdhQ7/Q7 were noted; GLN was able to mediate the activation of p65, Akt, p38, and CREB in HT22 and p65, Akt, and p38 in STHdhQ7/Q7 cells. Our accumulated findings suggest that GLN may increase learning and memory functions by inducing FGF21 production in the brain. This induction appears to be mediated, at least in part, through GLN’s activation of the NF-κB, Akt, p38, and PKA/CREB pathways.

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Section: Discussionmentioning

confidence: 99%

“…Notably, GLN's ability to cross the BBB [26] suggests potential protective effects in the brain. In fact, GLN has been demonstrated to potentially act against pathologic conditions such as encephalomyelitis [27], learning and memory impairment [5], neuroinflammation, and ischemic brain injury [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Glucosamine Enhancement of Learning and Memory Functions by Promoting Fibroblast Growth Factor 21 Production

Chao,

Wu,

Yeh

et al. 2024

IJMS

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“…Neuronal loss of O-GlcNAcylation in OGT cKO mice leads to progressive neurodegeneration ( Wang et al, 2016 ). While a neuroprotective role in neurodegeneration is proposed ( Wang et al, 2016 , Wang et al, 2021 , Cardozo et al, 2023 , Muha et al, 2019 ), the specific role of the O-GlcNAc modification in brain organization is less clear. Reports suggest both age- and disease-related changes in the brain upon O-GlcNAc pathway modulation ( Wheatley et al, 2019 , Lee et al, 2021a , White et al, 2020 , Lagerlof, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase intellectual disability

Murray,

Davidson,

Ferenbach

et al. 2023

Preprint

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Most intellectual disabilities are caused by monogenic variation. Mutations in the O-GlcNAc transferase (OGT) gene have recently been linked to a novel congenital disorder of glycosylation (OGT-CDG), involving symptoms of possible neuroectodermal origin. To test the hypothesis that pathology is linked to defects in differentiation during early embryogenesis, we developed an OGT-CDG induced pluripotent stem cell lines together with an isogenic controls generated by CRISPR/Cas9 gene-editing. Although the OGT-CDG variant leads to a significant decrease in OGT and O-GlcNAcase protein levels, there were no changes in differentiation potential or stemness. However, differentiation into ectoderm resulted in significant differences in O-GlcNAc homeostasis. Further differentiation to neuronal stem cells revealed differences in morphology between patient and control lines, accompanied by disruption of the O-GlcNAc pathway. This suggests a critical role for O-GlcNAcylation in early neuroectoderm architecture, with robust compensatory mechanisms in the earliest stages of stem cell differentiation.

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“…Reinforcing the relevance of Tau and α -syn in stroke, it has been observed that Tau and α -syn knockout mice exhibit significantly smaller brain damage after transient focal ischemia when compared to wild-type mice [ 73 , 82 , 87 ]. Moreover, reducing Tau hyperphosphorylation with GSK-3 β inhibitors such as nimodipine or by the administration of glucosamine, which by promoting O-GlcNAcylation antagonizes phosphorylation, has shown neuroprotective effects in rodent models of ischemia [ 20 , 87 ]. Additionally, task-specific training rehabilitation and an enriched environment improved functional deficits and reduced Tau-phosphorylation and neuroinflammation in the phototrombotic ischemia rat model [ 67 ], suggesting that brain plasticity mechanisms may modulate Tau pathology following brain ischemia.…”

Section: The Contribution Of a β Tau And ...mentioning

confidence: 99%

The contribution of β-amyloid, Tau and α-synuclein to blood–brain barrier damage in neurodegenerative disorders

Wu,

Bogale,

Koistinaho

et al. 2024

Acta Neuropathol

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Central nervous system (CNS) accumulation of fibrillary deposits made of Amyloid β (Aβ), hyperphosphorylated Tau or α-synuclein (α-syn), present either alone or in the form of mixed pathology, characterizes the most common neurodegenerative diseases (NDDs) as well as the aging brain. Compelling evidence supports that acute neurological disorders, such as traumatic brain injury (TBI) and stroke, are also accompanied by increased deposition of toxic Aβ, Tau and α-syn species. While the contribution of these pathological proteins to neurodegeneration has been experimentally ascertained, the cellular and molecular mechanisms driving Aβ, Tau and α-syn-related brain damage remain to be fully clarified. In the last few years, studies have shown that Aβ, Tau and α-syn may contribute to neurodegeneration also by inducing and/or promoting blood–brain barrier (BBB) disruption. These pathological proteins can affect BBB integrity either directly by affecting key BBB components such as pericytes and endothelial cells (ECs) or indirectly, by promoting brain macrophages activation and dysfunction. Here, we summarize and critically discuss key findings showing how Aβ, Tau and α-syn can contribute to BBB damage in most common NDDs, TBI and stroke. We also highlight the need for a deeper characterization of the role of these pathological proteins in the activation and dysfunction of brain macrophages, pericytes and ECs to improve diagnosis and treatment of acute and chronic neurological disorders.

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Regulation of Tau protein phosphorylation by glucosamine-induced O-GlcNAcylation as a neuroprotective mechanism in a brain ischemia-reperfusion model

Cited by 7 publications

References 36 publications

Glucosamine Enhancement of Learning and Memory Functions by Promoting Fibroblast Growth Factor 21 Production

Glucosamine Enhancement of Learning and Memory Functions by Promoting Fibroblast Growth Factor 21 Production

Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase intellectual disability

The contribution of β-amyloid, Tau and α-synuclein to blood–brain barrier damage in neurodegenerative disorders

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