The Role of PI3K/Akt and ERK in Neurodegenerative Disorders

Nand, Sachchida; Dilnashin, Hagera; Birla, Hareram; Singh, Sangeeta; Zahra, Walia; Rathore, Aaina Singh; Singh, Brijesh Kumar; Singh, Surya Pratap

doi:10.1007/s12640-019-0003-y

Cited by 325 publications

(200 citation statements)

References 171 publications

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“…viability and inhibiting senescence, ageing and death [2,[6][7][8], and is associated with normal and abnormal physiological activity. Dysfunction of this pathway is related to not only the occurrence and development of tumours but also many other human diseases, such as leukaemia, diabetes, and schizophrenia [9][10][11]. Researchers have gradually gained a strong understanding of PI3K/AKT/mTOR signalling pathway regulation and function and agree that thoroughly elucidating the mechanism of PI3K/AKT/mTOR signal transmission and the related upstream and downstream molecules is necessary [12][13][14].…”

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confidence: 99%

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

et al. 2020

Cell Biosci

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The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism and angiogenesis. Compared with those of other signalling pathways, the components of the PI3K/AKT/mTOR signalling pathway are complicated. The regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway are important in many human diseases, including ischaemic brain injury, neurodegenerative diseases, and tumours. PI3K/AKT/mTOR signalling pathway inhibitors include single-component and dual inhibitors. Numerous PI3K inhibitors have exhibited good results in preclinical studies, and some have been clinically tested in haematologic malignancies and solid tumours. In this review, we briefly summarize the results of research on the PI3K/AKT/mTOR pathway and discuss the structural composition, activation, communication processes, regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway in the pathogenesis of neurodegenerative diseases and tumours.

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confidence: 99%

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

et al. 2020

Cell Biosci

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“…Therefore, it seems likely that IR signalling is the primary pathological event following STZ-icv treatment, while a decrease in insulin synthesis comes as a secondary pathology, contributing to aggravation and progression of neurodegeneration. This hypothesis is in line with the findings of disturbed PI3K/AKT signalling pathway in neurodegeneration (as reviewed elsewhere, Rai et al 2019). The impaired signal is further transduced to GSK3 enzyme involved in dysregulation of AD-linked Aβ homeostasis and tau hyperphosphorylation (Martinez and Perez 2013), but also in α-Syn-mediated neurodegeneration in PD ).…”

Section: Insulin and Dopamine Signalling Interplay In Non-transgenic supporting

confidence: 87%

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease

et al. 2020

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Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common chronic neurodegenerative disorders, characterized by motoric dysfunction or cognitive decline in the early stage, respectively, but often by both symptoms in the advanced stage. Among underlying molecular pathologies that PD and AD patients have in common, more attention is recently paid to the central metabolic dysfunction presented as insulin resistant brain state (IRBS) and altered cerebral glucose metabolism, both also explored in animal models of these diseases. This review aims to compare IRBS and alterations in cerebral glucose metabolism in representative non-transgenic animal PD and AD models. The comparison is based on the selectivity of the neurotoxins which cause experimental PD and AD, towards the cellular membrane and intracellular molecular targets as well as towards the selective neurons/non-neuronal cells, and the particular brain regions. Mitochondrial damage and coexpression of insulin receptors, glucose transporter-2 and dopamine transporter on the membrane of particular neurons as well as astrocytes seem to be the key points which are further discussed in a context of alterations in insulin signalling in the brain and its interaction with dopaminergic transmission, particularly regarding the time frame of the experimental AD/ PD pathology appearance and the correlation with cognitive and motor symptoms. Such a perspective provides evidence on IRBS being a common underlying metabolic pathology and a contributor to neurodegenerative processes in representative non-transgenic animal PD and AD models, instead of being a direct cause of a particular neurodegenerative disorder.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…There have been numerous studies on the relationship between increased Aβ level and activation of ERK pathway, suggesting that ERK signal could be related to AD [51][52][53]. Chronic activation of ERK pathway was found in the hippocampus slide of the Aβ overexpressing AD transgenic animal model [51], moreover, Kirouac et al reported that the level of p-ERK in AD patients' brains increased as AD progressed [52]. Park et al showed that Asiatic acid inhibited methamphetamine-induced neuroin ammation through blocking of ERK pathway [53].…”

Section: Discussionmentioning

confidence: 99%

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

Ham

Lee

Yun

et al. 2020

Preprint

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Background Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. We have previously demonstrated that the 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), the inhibitor of CHI3L1, has an inhibitory effect on memory impairment in Αβ infusion mouse model and on LPS-induced neuroinflammation in the murine BV-2 microglia and primary cultured astrocyte. Methods In the present study, we investigated that the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and more detailed correlation of CHI3L1 and AD. To investigate the effects of K284-6111 on memory dysfunction, we administered K284-6111 (3 mg/kg, p.o.) daily for four weeks to Tg2576, followed by behavioral tests of water maze test, probe test, and passive avoidance test.Results Administration of K284-6111 alleviated memory impairment in Tg2576 mice and had the effect of reducing accumulation of Aβ and neuroinflammatory responses in the mouse brain. K284-6111 treatment also selectively inactivated ERK and NF-κB pathways, which were activated when CHI3L1 was overexpressed, in mouse brain and in BV-2 cells. Web-based gene network analysis and our results of gene expression level in BV-2 cells showed that CHI3L1 is closely correlated with PTX3. Our result revealed that knockdown of PTX3 has inhibitory effect on the production of inflammatory proteins and cytokines, and on the phosphorylation of ERK and IκBα.Conclusion These results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 through blocking ERK dependent PTX3 pathway.

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The Role of PI3K/Akt and ERK in Neurodegenerative Disorders

Cited by 325 publications

References 171 publications

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

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