Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance

Chen, Jinliang; Luo, Can; Pu, Die; Zhang, Guoqiang; Zhao, Yutong; Sun, Yue; Zhao, Kun; Liao, Zhiyin; Lv, An-Kang; Zhu, Shiyu; Zhou, Jing; Xiao, Qian

doi:10.1016/j.expneurol.2018.09.008

Cited by 92 publications

(50 citation statements)

References 45 publications

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“…Oral antidiabetic agents have yielded promising results when tested in disease models. The gluconeogenesis inhibitor molecule metformin extends lifespan in mice, lowers hyperphosphorylated τ in a diabetes mouse model, and reverses AD features in APP/PS1 mice (Chen et al, ; Martin‐Montalvo et al, ; Ou et al, ). Glucagon‐like peptide 1 (GLP1) receptor agonists act as an insulin sensitizing hormone and show neuroprotective effects (Li et al, ; Li et al, ).…”

Section: Treatment Strategies Targeting Mitochondria: Novel Approachementioning

confidence: 99%

“…Oral antidiabetic agents have yielded promising results when tested in disease models. The gluconeogenesis inhibitor molecule metformin extends lifespan in mice, lowers hyperphosphorylated τ in a diabetes mouse model, and reverses AD features in APP/PS1 mice (Chen et al, 2019;Martin-Montalvo et al, 2013;Ou et al, 2018).…”

Section: Ad Drug Development Pipeline: Bioenergetics Beyond Mitochomentioning

confidence: 99%

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Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Ortiz

Swerdlow

2019

British J Pharmacology

333

178

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Dysfunction of cell bioenergetics is a common feature of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Disrupted energy utilization implicates mitochondria at its nexus. This review summarizes some of the evidence that points to faulty mitochondrial function in AD and highlights past and current therapeutic development efforts. Classical neuropathological hallmarks of disease (β‐amyloid and τ) and sporadic AD risk genes (APOE) may trigger mitochondrial disturbance, yet mitochondrial dysfunction may incite pathology. Preclinical and clinical efforts have overwhelmingly centred on the amyloid pathway, but clinical trials have yet to reveal clear‐cut benefits. AD therapies aimed at mitochondrial dysfunction are few and concentrate on reversing oxidative stress and cell death pathways. Novel research efforts aimed at boosting mitochondrial and bioenergetic function offer an alternative treatment strategy. Enhancing cell bioenergetics in preclinical models may yield widespread favourable effects that could benefit persons with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Section: Treatment Strategies Targeting Mitochondria: Novel Approachementioning

confidence: 99%

“…Oral antidiabetic agents have yielded promising results when tested in disease models. The gluconeogenesis inhibitor molecule metformin extends lifespan in mice, lowers hyperphosphorylated τ in a diabetes mouse model, and reverses AD features in APP/PS1 mice (Chen et al, 2019;Martin-Montalvo et al, 2013;Ou et al, 2018).…”

Section: Ad Drug Development Pipeline: Bioenergetics Beyond Mitochomentioning

confidence: 99%

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Ortiz

Swerdlow

2019

British J Pharmacology

333

178

View full text Add to dashboard Cite

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“…Thus, while it increases the production of the AD-associated neurotoxic peptide A, by upregulation of the β-site APP cleaving enzyme 1 (BACE-1) activity [138], it results protective in Aβ-driven models of AD, in which it efficiently decreases microglia and astrocyte activation and NF-κB signaling [139]. Moreover, it reduces the phosphorylation of Tau protein, the other neurotoxic protein accumulated in AD, by activating the phosphatase PP2A [140] and is able to induce the autophagy mediated clearance of toxic aggregates [141]. Therefore, the use of metformin in AD patients, even though it could have potential neuroinflammatory properties, should be taken with caution.…”

Section: Metforminmentioning

confidence: 99%

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

Gabandé‐Rodríguez

Heras

Mittelbrunn

2019

Cells

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Mitochondrial metabolism and autophagy are two of the most metabolically active cellular processes, playing a crucial role in regulating organism longevity. In fact, both mitochondrial dysfunction or autophagy decline compromise cellular homeostasis and induce inflammation. Calorie restriction (CR) is the oldest strategy known to promote healthspan, and a plethora of CR mimetics have been used to emulate its beneficial effects. Herein, we discuss how CR and CR mimetics, by modulating mitochondrial metabolism or autophagic flux, prevent inflammatory processes, protect the intestinal barrier function, and dampen both inflammaging and neuroinflammation. We outline the effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade and how these anti-inflammatory properties could be involved in their ability to increase resilience to age-associated diseases.

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“…Interestingly, a recent study by Chen et al clearly showed metformin reduces Aβ burden by AMPK-induced enhancement of autophagy. is was further consolidated by a genetic study in which neurons from AMPKα2 knockout mice showed increased Aβ generation [63].…”

Section: Ampk and Aβ Metabolismmentioning

confidence: 99%

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

Assefa

Tafere

Wondafrash

et al. 2020

BioMed Research International

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Alzheimer’s disease is a multifactorial neurodegenerative disease characterized by progressive cognitive dysfunction. It is the most common form of dementia. The pathologic hallmarks of the disease include extracellular amyloid plaque, intracellular neurofibrillary tangles, and oxidative stress, to mention some of them. Despite remarkable progress in the understanding of the pathogenesis of the disease, drugs for cure or disease-modifying therapy remain somewhere in the distance. From recent time, the signaling molecule AMPK is gaining enormous attention in the AD drug research. AMPK is a master regulator of cellular energy metabolism, and recent pieces of evidence show that perturbation of its function is highly ascribed in the pathology of AD. Several drugs are known to activate AMPK, but their effect in AD remains to be controversial. In this review, the current shreds of evidence on the effect of AMPK activators in Aβ accumulation, tau aggregation, and oxidative stress are addressed. Positive and negative effects are reported with regard to Aβ and tauopathy but only positive in oxidative stress. We also tried to dissect the molecular interplays where the bewildering effects arise from.

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Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance

Cited by 92 publications

References 45 publications

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

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