Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling

Kickstein, Eva; Krauß, Sybille; Thornhill, Paul; Rutschow, Désirée; Zeller, Raphael; Sharkey, John; Williamson, Richard A.; Fuchs, Melanie; Köhler, Andrea; Glossmann, Hartmut; Schneider, Rainer; Sutherland, Calum; Schweiger, Susann

doi:10.1073/pnas.0912793107

Cited by 362 publications

(298 citation statements)

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“…While initial reports indicate that metformin increases the levels of brain Aβ by upregulating β-site APP cleaving enzyme 1 (BACE1) [125], some studies show that metformin attenuated AD-like changes and also reduced tau phosphorylation [126][127][128].…”

Section: Anti-diabetes Drugsmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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Section: Anti-diabetes Drugsmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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“…SDS-stable, high-molecular-weight tau oligomers are believed to be more toxic to neurons than PHFs (Lasagna-Reeves et al, 2011a;Henkins et al, 2012;Ward et al, 2012). Multiple antibodies, including Tau-5, T22, AT8, tau oligomer complex 1 (TOC1), and tau oligomer-specific monoclonal antibodies (TOMAs), have been used to detect tau species in the range of 100 -170 kDa, which have been termed tau multimers, oligomers, or highmolecular-weight tau-immunoreactive bands by different investigators (Berger et al, 2007;, 2011b; Sahara et al, 2013; Castillo-Carranza et al, 2014a,b; Ward et al, 2014).…”

Section: Cast Overexpression Inhibits Abnormal Tau Proteolysis By Calmentioning

confidence: 99%

“…Multiple antibodies, including Tau-5, T22, AT8, tau oligomer complex 1 (TOC1), and tau oligomer-specific monoclonal antibodies (TOMAs), have been used to detect tau species in the range of 100 -170 kDa, which have been termed tau multimers, oligomers, or highmolecular-weight tau-immunoreactive bands by different investigators (Berger et al, 2007;, 2011b; Sahara et al, 2013; Castillo-Carranza et al, 2014a,b; Ward et al, 2014). Using Tau-5, AT8, and PHF1 antibodies, we observed putative tau oligomer bands in the range of 100 -300 kDa .…”

Section: Cast Overexpression Inhibits Abnormal Tau Proteolysis By Calmentioning

confidence: 99%

“…Altered activities of cdk5, ERK1/2, GSK3␤, and PP2A (phosphatase 2A) contribute to pathological tau hyperphosphorylation and have disruptive effects on neuronal cell function, leading to neurodegeneration (Iqbal et al, 2010). Tau can also form neurotoxic oligomers which affect synaptic receptors or membranes Lasagna-Reeves et al, 2011a;Henkins et al, 2012;Ward et al, 2012) by disrupting vesicular trafficking or function, and may propagate toxicity transneuronally (de Calignon et al, 2012;Liu et al, 2012;Walker et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Specific Calpain Inhibition by Calpastatin Prevents Tauopathy and Neurodegeneration and Restores Normal Lifespan in Tau P301L Mice

Rao

McBrayer

Campbell

et al. 2014

Journal of Neuroscience

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Tau pathogenicity in Alzheimer's disease and other tauopathies is thought to involve the generation of hyperphosphorylated, truncated, and oligomeric tau species with enhanced neurotoxicity, although the generative mechanisms and the implications for disease therapy are not well understood. Here, we report a striking rescue from mutant tau toxicity in the JNPL3 mouse model of tauopathy. We show that pathological activation of calpains gives rise to a range of potentially toxic forms of tau, directly, and by activating cdk5. Calpain overactivation in brains of these mice is accelerated as a result of the marked depletion of the endogenous calpain inhibitor, calpastatin. When levels of this inhibitor are restored in neurons of JNPL3 mice by overexpressing calpastatin, tauopathy is prevented, including calpain-mediated breakdown of cytoskeletal proteins, cdk5 activation, tau hyperphosphorylation, formation of potentially neurotoxic tau fragments by either calpain or caspase-3, and tau oligomerization. Calpastatin overexpression also prevents loss of motor axons, delays disease onset, and extends survival of JNPL3 mice by 3 months to within the range of normal lifespan. Our findings support the therapeutic promise of highly specific calpain inhibition in the treatment of tauopathies and other neurodegenerative states.

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“…La metformine pourrait avoir un effet neuroprotecteur et prophylactique chez les patients avec une prédisposition pour la maladie d'Alzheimer [45]. L'hyperphosphorylation de la protéine tau associée aux microtubules est un élément majeur dans la pathogenèse de la maladie d'Alzheimer en provoquant les dégénérescences neurofibrillaires.…”

Section: Effet Neuroprotecteur De La Metformine Un Espoir Pour Les Munclassified

Les nouvelles promesses de la metformine

Foretz

Viollet

2014

Med Sci (Paris)

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> La metformine est l'antidiabétique oral de première intention lors de la prise en charge thérapeutique du diabète de type 2. Son mécanisme d'action est resté longtemps imprécis et commence seulement à être dévoilé. Des données épidémiologiques récentes ont montré que cet antidiabétique exerce également une protection cardiovasculaire et présente des propriétés antitumorales, indépendamment de son action sur la glycémie. Nous présentons dans cette revue les différents mécanismes d'action de la metformine dans ses effets bénéfiques sur la glycémie, les pathologies cardiovasculaires et le cancer. . Toutefois, ces découvertes sont éclip-sées par la découverte de l'insuline en 1921, et il faudra attendre la fin des années 1950 pour redécouvrir le potentiel clinique des biguanides dans le traitement du diabète. En 1957, Jean Sterne, un médecin français, réalisa les premiers essais cliniques chez l'homme de la metformine utilisée comme agent antidiabétique oral. Il démontra que, de toutes les autres biguanides testées, la metformine possèdait le meilleur rapport bénéfice/risque [2]. À la suite de ces travaux, la metformine fut commercialisée pour la première fois en France sous le nom évocateur de Glucophage par les laboratoires Aron en 1959. En 1958, la phenformine (phényl-éthylbiguanide) et la buformine (monobutylbiguanide) (Figure 1) sont privilégiées comme agents antidiabétiques, respectivement aux États-Unis et en Allemagne. Ces deux biguanides étaient plus actives que la metformine, mais, à la suite de plusieurs cas d'acidose lactique mortels et d'accidents cardiaques, la phenformine a été retirée du marché américain en 1976. Après confirmation d'une faible incidence de cas d'acidose lactique, la metformine a continué à être prescrite très largement en Europe. Les accidents liés à la prise de phenformine ont toutefois entaché la réputation de la metformine et empêché sa diffusion aux États-Unis. L'étude multicentrique britannique UKPDS (United Kingdom prospective diabetes study) permettra de confirmer la place de référence de la metformine dans le traitement du diabète 1 Inserm U1016, Institut Cochin, département d'endocrinologie, métabolisme et diabète, 24, rue du Faubourg Saint Jacques,

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Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling

Cited by 362 publications

References 40 publications

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Specific Calpain Inhibition by Calpastatin Prevents Tauopathy and Neurodegeneration and Restores Normal Lifespan in Tau P301L Mice

Les nouvelles promesses de la metformine

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