mTOR signaling as a molecular target for the alleviation of Alzheimer's disease pathogenesis

Rapaka, Deepthi; Bitra, Veera Raghavulu; Challa, Siva Reddy; Adiukwu, Paul Chukwuemeka

doi:10.1016/j.neuint.2022.105311

Cited by 35 publications

(52 citation statements)

References 206 publications

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“…mTOR also is involved in autophagy regulation [ 82 ]. More importantly, mTOR is a possible treatment for AD pathogenesis [ 17 ]. EGCG displayed a reduction of mTOR in western blot analysis.…”

Section: Discussionmentioning

confidence: 99%

“…The Phosphoinositide 3 Kinase/Protein Kinase B (PI3K-Akt) pathway modulates many microglial microenvironment cellular activities via its management of the mammalian mechanistic target of rapamycin (mTOR), which is a serine-threonine kinase involved in cellular metabolism, autophagy, aging, and nutrient regulation [ 16 ]. Furthermore, mTOR dysregulation has been linked to generating neurodegeneration as well as exacerbating protein accumulation (Tau protein accumulation and Amyloid beta (Aβ) in AD) [ 17 ]. Current research has led to the observation of phytochemical intervention, i.e., resveratrol and EGCG, in countering these signaling processes due to the chronic damage caused by aging and immunoregulatory insults.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Mechanisms of the Anti-Inflammatory Effects of Epigallocatechin 3-Gallate (EGCG) in LPS-Activated BV-2 Microglia Cells

et al. 2023

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Chronic neuroinflammation is associated with many neurodegenerative diseases, such as Alzheimer’s. Microglia are the brain’s primary immune cells, and when activated, they release various proinflammatory cytokines. Several natural compounds with anti-inflammatory and antioxidant properties, such as epigallocatechin 3-gallate (EGCG), may provide a promising strategy for inflammation-related neurodegenerative diseases involving activated microglia cells. The objective of the current study was to examine the molecular targets underlying the anti-inflammatory effects of EGCG in activated microglia cells. BV-2 microglia cells were grown, stimulated, and treated with EGCG. Cytotoxicity and nitric oxide (NO) production were evaluated. Immunoassay, PCR array, and WES™ Technology were utilized to evaluate inflammatory, neuroprotective modulators as well as signaling pathways involved in the mechanistic action of neuroinflammation. Our findings showed that EGCG significantly inhibited proinflammatory mediator NO production in LPS-stimulated BV-2 microglia cells. In addition, ELISA analysis revealed that EGCG significantly decreases the release of proinflammatory cytokine IL-6 while it increases the release of TNF-α. PCR array analysis showed that EGCG downregulated MIF, CCL-2, and CSF2. It also upregulated IL-3, IL-11, and TNFS10. Furthermore, the analysis of inflammatory signaling pathways showed that EGCG significantly downregulated mRNA expression of mTOR, NF-κB2, STAT1, Akt3, CCL5, and SMAD3 while significantly upregulating the expression of mRNA of Ins2, Pld2, A20/TNFAIP3, and GAB1. Additionally, EGCG reduced the relative protein expression of NF-κB2, mTOR, and Akt3. These findings suggest that EGCG may be used for its anti-inflammatory effects to prevent neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of the Anti-Inflammatory Effects of Epigallocatechin 3-Gallate (EGCG) in LPS-Activated BV-2 Microglia Cells

et al. 2023

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“…While our five kinases have been implicated in traditional AD pathology (such as tau phosphorylation, amyloid processing), there is emerging evidence for a role in mediating key metabolic pathways. In fact, the three shared pathways in the underrepresented kinases converge on classical pathways mediating metabolic pathways: FoxO, Prolactin, and Cellular senescence (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

Henkel

Joyce

Shedroff

et al. 2022

Preprint

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Neurons and astrocytes derived from Alzheimers Disease (AD) patient induced pluripotent stem cells are an evolving technology used to study the pathogenesis and etiology of AD. As the utility of mouse models of AD are increasingly coming into questions, using iPSC technology may offer an opportunity to study this disease with human substrates. Herein, we using a hypothesis generating platform, the PamGene12 Kinome Array, to identify core protein kinases in neurons and astrocytes derived from familial AD patient iPSCs. We identified five core protein kinases in these cells and examined the pathways in which they are enriched. Importantly, we complement our findings using an in-silico approach with postmortem AD brain datasets. While these protein kinases have been conceptualized in the context of traditional AD pathology, they have not been explored in the context of aberrant signaling in the pathophysiology of the disease.

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“…Raptor interacts with the HEAT repeats of mTOR in addition to binding with its extreme carboxyl terminal, whereas PRAS40 binds to Raptor. The binding of Rheb-GTP to the HEAT domain leads to the activation of mTORC1 kinase [ 24 ].…”

Section: P13k/akt/mtor Pathwaymentioning

confidence: 99%

“…Alterations in the mTOR pathway are related to numerous neurological disorders [ 22 , 23 ]. The PI3K/Akt/mTOR signaling cascade has been implicated in the pathogenesis of various neurodegenerative and neuropsychiatric disorders, e.g., Alzheimer’s disease [ 24 ], Parkinson’s disease [ 25 ], epilepsy [ 26 ], tuberous sclerosis complex (TSC) [ 11 ], fragile X syndrome [ 10 ], depression [ 27 ], schizophrenia [ 28 ] and bipolar disorder [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

mTOR Signaling Disruption and Its Association with the Development of Autism Spectrum Disorder

et al. 2023

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication along with repetitive stereotypic behaviors. Currently, there are no specific biomarkers for diagnostic screening or treatments available for autistic patients. Numerous genetic disorders are associated with high prevalence of ASD, including tuberous sclerosis complex, phosphatase and tensin homolog, and fragile X syndrome. Preclinical investigations in animal models of these diseases have revealed irregularities in the PI3K/Akt/mTOR signaling pathway as well as ASD-related behavioral defects. Reversal of the downstream molecular irregularities, associated with mTOR hyperactivation, improved the behavioral deficits observed in the preclinical investigations. Plant bioactive molecules have shown beneficial pre-clinical evidence in ASD treatment by modulating the PI3K/Akt/mTOR pathway. In this review, we summarize the involvement of the PI3K/Akt/mTOR pathway as well as the genetic alterations of the pathway components and its critical impact on the development of the autism spectrum disorder. Mutations in negative regulators of mTORC1, such as TSC1, TSC2, and PTEN, result in ASD-like phenotypes through the disruption of the mTORC1-mediated signaling. We further discuss the various naturally occurring phytoconstituents that have been identified to be bioactive and modulate the pathway to prevent its disruption and contribute to beneficial therapeutic effects in ASD.

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mTOR signaling as a molecular target for the alleviation of Alzheimer's disease pathogenesis

Cited by 35 publications

References 206 publications

Molecular Mechanisms of the Anti-Inflammatory Effects of Epigallocatechin 3-Gallate (EGCG) in LPS-Activated BV-2 Microglia Cells

Molecular Mechanisms of the Anti-Inflammatory Effects of Epigallocatechin 3-Gallate (EGCG) in LPS-Activated BV-2 Microglia Cells

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimer’s Disease

mTOR Signaling Disruption and Its Association with the Development of Autism Spectrum Disorder

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