Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction

Chiang, Ming‐Chang; Cheng, Yi-Chuan; Chen, Shiang-Jiuun; Yen, Chia‐Hui; Huang, Rong‐Nan

doi:10.1016/j.yexcr.2016.08.013

Cited by 95 publications

(53 citation statements)

References 84 publications

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“…Therapeutic interventions seeking to enhance astrocytic lactate transport may provide a more fruitful endeavour. MCT1 knockout mice show deficits in long term memory (109) Metformin, the antidiabetic drug, has received a lot of attention with regards to its potential act as a novel therapeutic strategy in managing AD (112)(113)(114). This links into the emerging hypothesis that AD should be classed as a third type of diabetes (115,116).…”

Section: Relevance To Alzheimer's Diseasementioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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Section: Relevance To Alzheimer's Diseasementioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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“…On the other hand, metformin treatment of cells over expressing alpha synuclein (a major component in many forms of Parkinson's) has proved effective in increasing cell viability and abolished the toxic effects of alpha synucelin [86]. In addition metformin has shown to be protective in other models of Parkinson's [87,88] and Alzheimer's [89].…”

Section: Metforminmentioning

confidence: 99%

Modulating Mitophagy in Mitochondrial Disease

Dombi

Mortiboys

Poulton

2019

CMC

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Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may effect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function.

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“…AMPK plays an important role in the regulation of intracellular event such as glucose uptake, metabolism of lipids and mitochondrial biogenesis. Since there's a connection between AD pathogenesis and cellular mechanisms of energy homeostasis, targeting AMPK pathway in human neural stem cells could be a therapeutic option for AD [70]. The ability of metformin to decrease the development of AD was studied through one-year administration of metformin to APP transgenic mice, which over express mutant APP and serve as model for AD.…”

Section: Classes Of Anti-diabetic Drugs As Potential Treatments For Amentioning

confidence: 99%

The Use of Anti-Diabetic Drugs in Alzheimer’s Disease, New Therapeutic Options and Future Perspective

Ibrahim¹,

Hassan²

2018

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Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive loss of memory, confusion, inability of speech and decline in the cognitive behavior. It is considered one of the most common forms of dementia. Clinical studies and preclinical data in the last decade proved that AD and Diabetes mellitus share a pathophysiological pathway, indicating that insulin resistance, oxidative stress and inflammatory response would increase the risks of developing AD in diabetic patients. This review presents briefly the etiology of AD and Diabetes, discusses the possible theories about the interplaying risk factors and the mechanism of action of anti-diabetic medications recommended for the treatment of AD. It is concluded that antidiabetics have good potential to improve dementia, especially in earlier AD stages. However, many of the underlying intricate molecular pathways are still unclear and thus thorough future research is required.

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Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction

Cited by 95 publications

References 84 publications

Astrocytic transporters in Alzheimer's disease

Astrocytic transporters in Alzheimer's disease

Modulating Mitophagy in Mitochondrial Disease

The Use of Anti-Diabetic Drugs in Alzheimer’s Disease, New Therapeutic Options and Future Perspective

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