Aβ peptide secretion is reduced by Radix Polygalae-induced autophagy via activation of the AMPK/mTOR pathway

Zhao, Huan; Wang, Zhi‐Cheng; Wang, Kui‐Feng; Chen, Xiaoyu

doi:10.3892/mmr.2015.3781

Cited by 49 publications

(30 citation statements)

References 37 publications

(48 reference statements)

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“…AMPK also phosphorylates TSC2 to inhibit mTORC1 activity (19, 326). In the nervous system, AMPK activation can limit Aβ production and secretion (327, 328), reduce oxidative stress parameters in diabetic animals with cognitive dysfunction (329), limit infarct size in models of stroke (330), be responsible for lifespan extension (331), may modulate neuroinflammation (332), and prevent memory impairment (193). Yet, AMPK activation is not consistently beneficial.…”

Section: Signaling Pathways Of Erythropoietinmentioning

confidence: 99%

Regeneration in the nervous system with erythropoietin

Maiese¹

2016

Front Biosci

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Globally, greater than 30 million individuals are afflicted with disorders of the nervous system accompanied by tens of thousands of new cases annually with limited, if any, treatment options. Erythropoietin (EPO) offers an exciting and novel therapeutic strategy to address both acute and chronic neurodegenerative disorders. EPO governs a number of critical protective and regenerative mechanisms that can impact apoptotic and autophagic programmed cell death pathways through protein kinase B (Akt), sirtuins, mammalian forkhead transcription factors, and wingless signaling. Translation of the cytoprotective pathways of EPO into clinically effective treatments for some neurodegenerative disorders has been promising, but additional work is necessary. In particular, development of new treatments with erythropoiesis-stimulating agents such as EPO brings several important challenges that involve detrimental vascular outcomes and tumorigenesis. Future work that can effectively and safely harness the complexity of the signaling pathways of EPO will be vital for the fruitful treatment of disorders of the nervous system.

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Section: Signaling Pathways Of Erythropoietinmentioning

confidence: 99%

Regeneration in the nervous system with erythropoietin

Maiese¹

2016

Front Biosci

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“…Equally important is the impact of aging on the nervous system (18). Learning and memory capacity can decline with loss of hippocampal and cortical neurons (19, 20) and may ultimately result in progressive neurodegenerative disease (21–25). …”

Section: Increased Lifespan Degenerative Disorders and Cell Injurymentioning

confidence: 99%

“…As a result, cardiomyopathy is limited in experimental models of DM (108) and endothelial cell senescence is reduced during applications of metformin (109). AMPK maintains metabolic function of cells, prevents atherosclerosis, modulates immune system activity, and can prevent β-amyloid (Aβ) accumulation (25, 40, 110–113). AMPK activation also may improve memory retention in models of AD and DM (114).…”

Section: The Mechanistic Target Of Rapamycin (Mtor)mentioning

confidence: 99%

“…Loss of mTOR activity (105) or components of this pathway, such as mTORC2, can result in apoptotic cell death (130). Activation of either mTOR or downstream pathways that involve p70S6K can protect against Aβ toxicity (21, 25, 97, 117, 145–148), cerebral ischemia (149, 150), and oxidative stress exposure (151, 152). During metabolic disease such as DM (28), mTOR activation can prevent the development of atherosclerosis (153) and through glucagon-like peptide-1 agonists can protect pancreatic β-cells from cholesterol mediated apoptotic cell injury (152).…”

Section: Targeting Cell Death Through Mtormentioning

confidence: 99%

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Erythropoietin and mTOR: A “One-Two Punch” for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

Maiese¹

2016

CNR

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Life expectancy continues to increase throughout the world, but is accompanied by a rise in the incidence of non-communicable diseases. As a result, the benefits of an increased lifespan can be limited by aging-related disorders that necessitate new directives for the development of effective and safe treatment modalities. With this objective, the mechanistic target of rapamycin (mTOR), a 289-kDa serine/threonine protein, and its related pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), proline rich Akt substrate 40 kDa (PRAS40), AMP activated protein kinase (AMPK), Wnt signaling, and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), have generated significant excitement for furthering novel therapies applicable to multiple systems of the body. Yet, the biological and clinical outcome of these pathways can be complex especially with oversight of cell death mechanisms that involve apoptosis and autophagy. Growth factors, and in particular erythropoietin (EPO), are one avenue under consideration to implement control over cell death pathways since EPO can offer potential treatment for multiple disease entities and is intimately dependent upon mTOR signaling. In experimental and clinical studies, EPO appears to have significant efficacy in treating several disorders including those involving the developing brain. However, in mature populations that are affected by aging-related disorders, the direction for the use of EPO to treat clinical disease is less clear that may be dependent upon a number of factors including the understanding of mTOR signaling. Continued focus upon the regulatory elements that control EPO and mTOR signaling could generate critical insights for targeting a broad range of clinical maladies.

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“…Role of the AMPK pathway on neuroprotection is poorly understood and a subject of debate. Some studies have found that AMPK activation induced amyloidogenesis, whereas others have found that AMPK activation induced autophagy, resulting in Aβ clearance [593][594][595][596]. Moreover, a range of natural products and drugs that up-regulate the AMPK pathway, such as phytic acid, arctigenin and resveratrol, also reduced Aβ-proteotoxicity and improved memory function in mouse models [597].…”

Section: Discussionmentioning

confidence: 99%

Metabolic study of Alzheimer’s disease using mutant C. elegans

Ahmad¹

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Alzheimer's disease (AD) is associated with chronic neurodegeneration and is the cause of the most common form of dementia. The main hallmarks of AD are aggregates of amyloid beta (Aβ) and formation of hyperphosphorylated tau neurofibrillary tangles (NFTs). Unfortunately, after more than 100 years of research the exact cause(s) and mechanisms involved in AD progression remain unclarified. Evidence indicates that impaired mitochondrial bioenergetics may precede by decades, the neurodegeneration and cognitive decline associated with AD. Moreover, a genetic association of the core metabolic enzyme dihydrolipoamide dehydrogenase (DLD) with late-onset AD and reduced activity of DLD-containing enzymes suggests glucose hypo-metabolism as a possible cause of AD. Contrary to this, improvements of AD symptoms under caloric restriction or other means of reducing-glucose dependent energy metabolism supports an alternative hypothesis that a decrease in glucose metabolism may be protective. In the present study, we used mutant Caenorhabditis elegans (C. elegans) to investigate the effect of glucose metabolism on AD progression. We initially looked at the role of suppressed DLD-1, and then we focused on the effect of high glucose in AD pathogenesis.Transgenic expression of Aβ in C. elegans causes both phenotypic and behavioral defects and results in accumulation of toxic Aβ oligomers, culminating in protein aggregation as is normally associated with AD pathophysiology. Aβ expression in worm muscle causes agedependent progressive paralysis and impaired acetylcholine neurotransmission while neuronal Aβ expression results in defective chemotaxis and impaired serotonin sensitivity as well as reduced fecundity and egg hatching. Suppression of the dld-1 gene alleviated paralysis, improved acetylcholine neurotransmission, enhanced chemotaxis and restored normal sensitivity to serotonin.dld-1 gene suppression also protects vitality as indicated by improved fecundity and egg hatching.Interestingly, protective effects of dld-1 suppression could be reversed using the calcium ionophore (CaI), indicating that the protective mechanism involves calcium signaling. Each of these beneficial effects of dld-1 gene suppression could be mimicked using a specific, small molecule inhibitor of the DLD-1 enzyme, 5-methoxyindole-2-carboxylic acid (MICA).High glucose levels are associated with the metabolic disorder, diabetes, which is a major risk factor for AD. In fact, it has been suggested that AD is a neural form of diabetes, type 3 diabetes. If true, drugs used to treat diabetes could act as possible treatments for AD. In this study, I investigated the effect of elevated glucose, the glucose metabolism inhibitor, 2-deoxy-d-glucose ii (2DOG) as well as the anti-diabetes drugs, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on AD progression. Elevated glucose in the growth medium induced hyperactivity, which interfered with the paralysis assays, but it was seen to impair cholinergic neurotransmission, egg laying and hatc...

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Aβ peptide secretion is reduced by Radix Polygalae-induced autophagy via activation of the AMPK/mTOR pathway

Cited by 49 publications

References 37 publications

Regeneration in the nervous system with erythropoietin

Regeneration in the nervous system with erythropoietin

Erythropoietin and mTOR: A “One-Two Punch” for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

Metabolic study of Alzheimer’s disease using mutant C. elegans

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