Pioglitazone Reduces β Amyloid Levels via Inhibition of PPARγ Phosphorylation in a Neuronal Model of Alzheimer’s Disease

Quan, Qiankun; Qian, Yi‐Hua; Li, Xi; Li, Ming

doi:10.3389/fnagi.2019.00178

Cited by 37 publications

(45 citation statements)

References 67 publications

(83 reference statements)

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“…recently, a study demonstrated that pioglitazone inhibits the phosphorylation of PParγ at Ser273 in vitro by inhibiting cdK5 expression, which in turn affected the expression of PParγ target genes Ide and Bace1, thereby promoting aβ degradation and reducing aβ production. This reduced aβ levels in the brain, thereby exerting neuroprotective effects in an AD model (53). These findings indicate that TZds have neuroprotective effects against ad.…”

Section: Discussionmentioning

confidence: 78%

“…In the study, no experiments such as chromatin immunoprecipitation RT-qPCR, were performed to confirm whether CDK5 directly regulates PPARγ. However, our previous study reported that CDK5 regulates PPARγ ( 21 ), and performed co-immunoprecipitation experiments to confirm that Aβ promotes the binding of CDK5 to PPARγ ( 53 ). In addition, our previous study demonstrated that the PPARγ agonist pioglitazone inhibits PPARγ phosphorylation by inhibiting CDK5 expression, thereby promoting Aβ degradation and reducing Aβ production ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

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Ginsenoside Rg1 reduces β‑amyloid levels by inhibiting CD5K‑induced PPARγ phosphorylation in a neuron model of Alzheimer's disease

Quan

Jin

et al. 2020

Mol Med Rep

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The accumulation of β-amyloid peptides (aβ) in the brain is a hallmark of alzheimer's disease (ad). Studies have indicated that ginsenoside rg1, a primary component of ginseng (Panax ginseng), reduces brain aβ levels in an ad model through peroxisome proliferator-activated receptor γ (PParγ), thereby regulating the expression of insulin-degrading enzyme (Ide) and β-amyloid cleavage enzyme 1 (Bace1), which are PParγ target genes. However, the effects of ginsenoside rg1 on PParγ remain unclear. Since cyclin-dependent kinase 5 (cdK5) mediates PParγ phosphorylation in adipose tissue, this study aimed to investigate whether ginsenoside rg1 regulates PParγ target genes and reduces aβ levels by inhibiting PParγ phosphorylation through the cdK5 pathway. in the present study, a model of ad was established by treating primary cultured rat hippocampal neurons with aβ 1-42. The cells were pretreatment with ginsenoside rg1 and roscovitine, a cdK5-inhibitor, prior to the treatment with aβ 1-42. neuronal apoptosis was detected using Tunel staining. PParγ phosphorylation and protein expression levels of PParγ, cdK5, ide, Bace1, amyloid precursor protein (aPP) and aβ 1-42 were measured by western blotting. The mrna expression levels of PParγ, cdK5, ide, Bace1 and aPP were assessed using reverse transcription-quantitative Pcr. The results of the present study demonstrated that in an ad model induced by aβ 1-42 , ginsenoside Rg1 significantly decreased CDK5 expression, inhibited PParγ phosphorylation at serine 273, elevated ide expression, downregulated Bace1 and aPP expression, decreased aβ 1-42 levels and attenuated neuronal apoptosis. The cdK5 inhibitor, roscovitine, demonstrated similar effects. These results suggest that ginsenoside rg1 has neuroprotective properties and has potential for use in the treatment of ad.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg1 reduces β‑amyloid levels by inhibiting CD5K‑induced PPARγ phosphorylation in a neuron model of Alzheimer's disease

Quan

Jin

et al. 2020

Mol Med Rep

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“…Pioglitazone down-regulated CDK5 expression and PPARγ phosphorylation, and increased PPARγ expression, inhibiting BACE1 expression and Aβ production. The PPARγ antagonist GW9662 blocked these pioglitazone effects ( Quan et al, 2019b ), affirming they were mediated by the PPARγ receptor.…”

Section: Pparγ and Ad-related Risk Factorsmentioning

confidence: 90%

“…In both cell-based and in vivo models, PPARγ, but not PPARα or PPARδ ( Camacho et al, 2004 ), blocked the generation and release of Aβ peptides ( Sastre et al, 2003 , 2006 ; Liu et al, 2013 ; Gad et al, 2016 ; Quan et al, 2019b ) by blocking BACE1 mRNA and protein expression, and promoting Aβ peptide clearance ( Camacho et al, 2004 ). In vivo , PPARγ activation resulted in significantly reduced β-amyloid plaques ( Heneka et al, 2005 ; Escribano et al, 2010 ; O’Reilly and Lynch, 2012 ; Searcy et al, 2012 ; Liu et al, 2013 ; Quan et al, 2019b ). In vitro , the RXR ligand cis -retinoic acid alone was as effective as PPARγ agonists alone, including pioglitazone ( Camacho et al, 2004 ).…”

Section: Pparγ and Ad-related Risk Factorsmentioning

confidence: 99%

Reassessment of Pioglitazone for Alzheimer’s Disease

Saunders¹,

Burns²,

Gottschalk

2021

Front. Neurosci.

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Alzheimer’s disease is a quintessential ‘unmet medical need’, accounting for ∼65% of progressive cognitive impairment among the elderly, and 700,000 deaths in the United States in 2020. In 2019, the cost of caring for Alzheimer’s sufferers was $244B, not including the emotional and physical toll on caregivers. In spite of this dismal reality, no treatments are available that reduce the risk of developing AD or that offer prolonged mitiagation of its most devestating symptoms. This review summarizes key aspects of the biology and genetics of Alzheimer’s disease, and we describe how pioglitazone improves many of the patholophysiological determinants of AD. We also summarize the results of pre-clinical experiments, longitudinal observational studies, and clinical trials. The results of animal testing suggest that pioglitazone can be corrective as well as protective, and that its efficacy is enhanced in a time- and dose-dependent manner, but the dose-effect relations are not monotonic or sigmoid. Longitudinal cohort studies suggests that it delays the onset of dementia in individuals with pre-existing type 2 diabetes mellitus, which small scale, unblinded pilot studies seem to confirm. However, the results of placebo-controlled, blinded clinical trials have not borne this out, and we discuss possible explanations for these discrepancies.

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“…In recent years, PG has been used to improve some brain disorders. However, little is known about its neurotoxicity [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Toxicity of Pioglitazone on Mitochondria Isolated from Brain and Heart: An Analysis for Probable Drug-Induced Neurotoxicity and Cardiotoxicity

et al. 2020

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Pioglitazone (PG) is one of the thiazolidinedione (TZDs) drugs used in diabetic patients. TZDs are known as peroxisome proliferator-activated receptor gamma (PPARγ) agonists. Mitochondria are considered as one of the targets of these drugs. The mechanisms of the effect of PG on mitochondria are not well understood. In this study, we investigated the effect of PG on mitochondria isolated from brain and heart. Mitochondrial parameters such as succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) generation, collapse in mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release were evaluated. The results showed that PG at concentrations of 12.5, 25 and 50 µg/ml increased the generation of ROS, the collapse of MMP, mitochondrial swelling and the release of cytochrome c in mitochondria isolated from both brain and heart tissues. The underlying mechanisms of PG induced neuro-toxicity and cardio-toxicity may be associated with changes in mitochondrial function, ROS generation (oxidative stress), and changes in the mitochondrial membrane.

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Pioglitazone Reduces β Amyloid Levels via Inhibition of PPARγ Phosphorylation in a Neuronal Model of Alzheimer’s Disease

Cited by 37 publications

References 67 publications

Ginsenoside Rg1 reduces β‑amyloid levels by inhibiting CD5K‑induced PPARγ phosphorylation in a neuron model of Alzheimer's disease

Ginsenoside Rg1 reduces β‑amyloid levels by inhibiting CD5K‑induced PPARγ phosphorylation in a neuron model of Alzheimer's disease

Reassessment of Pioglitazone for Alzheimer’s Disease

Toxicity of Pioglitazone on Mitochondria Isolated from Brain and Heart: An Analysis for Probable Drug-Induced Neurotoxicity and Cardiotoxicity

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