Overexpression of p35 in Min6 pancreatic beta cells induces a stressed neuron-like apoptosis

Zheng, Yali; Y, Hu; Zhang, Aiping; Wang, Wei; Li, Bo; Amin, Niranjana D.; Grant, Philip; Pant, Harish C.

doi:10.1016/j.jns.2010.08.067

Cited by 18 publications

(32 citation statements)

References 32 publications

(73 reference statements)

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“…The effect also shares some features with the glucotoxic phenotype of pancreatic β cells which shut down insulin secretion in response to hyperactive Cdk5 [14, 25]. HG also evokes oxidative stress in neurons (i.e., increased ROS, decreased total glutathione and SOD activity) as well as inflammation and cell death, phenotypes consistent with those reported for patients and experimental animals [2, 9–13].…”

Section: Discussionsupporting

confidence: 58%

“…As a result, insulin secretion was inhibited and cells became apoptotic. Roscovitine treatment or co-infection with dominant negative Cdk5 increased insulin secretion and inhibited apoptosis [14]. It is note-worthy that deregulation and hyperactivation of Cdk5 has been suggested as contributing to the pathology seen in AD in a manner similar to that seen above.…”

Section: Introductionmentioning

confidence: 99%

“…Previously we reported that Cdk5 regulates insulin secretion in glucose stimulated pancreatic β cells [14]. Cells overexpressing p35, treated with high glucose (HG), showed induction of p25, the p35-derived truncated fragment which hyperactivates Cdk5 in neurons.…”

Section: Introductionmentioning

confidence: 99%

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TFP5, a Peptide Derived from p35, a Cdk5 Neuronal Activator, Rescues Cortical Neurons from Glucose Toxicity

Binukumar

Zheng

Shukla

et al. 2014

JAD

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Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer’s disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. Cyclin dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39, found principally in neurons and in pancreatic β cells. Recent studies suggest that Cdk5 hyperactivity is a possible link between neuropathology seen in AD and diabetes. Previously, we identified P5, a truncated 24-aa peptide derived from the Cdk5 activator p35, later modified as TFP5, so as to penetrate the blood-brain barrier after intraperitoneal injections in AD model mice. This treatment inhibited abnormal Cdk5 hyperactivity and significantly rescued AD pathology in these mice. The present study explores the potential of TFP5 peptide to rescue high glucose (HG)-mediated toxicity in rat embryonic cortical neurons. HG exposure leads to Cdk5- p25 hyperactivity and oxidative stress marked by increased reactive oxygen species production, and decreased glutathione levels and superoxide dismutase activity. It also induces hyperphosphorylation of tau, neuroinflammation as evident from the increased expression of inflammatory cytokines like TNF-α, IL-1β, and IL-6, and apoptosis. Pretreatment of cortical neurons with TFP5 before HG exposure inhibited Cdk5-p25 hyperactivity and significantly attenuated oxidative stress by decreasing reactive oxygen species levels, while increasing superoxide dismutase activity and glutathione. Tau hyperphosphorylation, inflammation, and apoptosis induced by HG were also considerably reduced by pretreatment with TFP5. These results suggest that TFP5 peptide may be a novel candidate for type 2 diabetes therapy.

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Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

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TFP5, a Peptide Derived from p35, a Cdk5 Neuronal Activator, Rescues Cortical Neurons from Glucose Toxicity

Binukumar

Zheng

Shukla

et al. 2014

JAD

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“…Glucotoxicity, which deteriorates functions of insulin on peripheral tissues and the secretion of insulin by beta cells is a critical factor of the pathophysiology of diabetes mellitus. In our previous studies, we showed that high glucose stimulates the increasing expression of p35 in Min6 cells and overexpressed p35 in HG, revealing the expression of p25, which led to decreased insulin secretion [17]. We also found a stressed neuron-like apoptosis with detection of p25 in the Min6 cells after exposing overexpressed p35 cells to a high glucose concentration [17].…”

Section: Introductionmentioning

confidence: 78%

“…In our previous studies, we showed that high glucose stimulates the increasing expression of p35 in Min6 cells and overexpressed p35 in HG, revealing the expression of p25, which led to decreased insulin secretion [17]. We also found a stressed neuron-like apoptosis with detection of p25 in the Min6 cells after exposing overexpressed p35 cells to a high glucose concentration [17]. Although the existence of p25 was clearly observed in our study, the role of Cdk5/p25 in pathogenesis to diabetes remains unclear; and whether inhibition of Cdk5/p25 activity can protect beta cells from pathology as it does with neurons.…”

Section: Introductionmentioning

confidence: 94%

Cdk5 Inhibitory Peptide (CIP) Inhibits Cdk5/p25 Activity Induced by High Glucose in Pancreatic Beta Cells and Recovers Insulin Secretion from p25 Damage

Zheng

et al. 2013

PLoS ONE

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Cdk5/p25 hyperactivity has been demonstrated to lead to neuron apoptosis and degenerations. Chronic exposure to high glucose (HG) results in hyperactivity of Cdk5 and reduced insulin secretion. Here, we set out to determine whether abnormal upregulation of Cdk5/p25 activity may be induced in a pancreatic beta cell line, Min6 cells. We first confirmed that p25 were induced in overexpressed p35 cells treated with HG and increased time course dependence. Next, we showed that no p25 was detected under short time HG stimulation (4–12 hrs), however was detectable in the long exposure in HG cells (24 hrs and 48 hrs). Cdk5 activity in the above cells was much higher than low glucose treated cells and resulted in more than 50% inhibition of insulin secretion. We confirmed these results by overexpression of p25 in Min6 cells. As in cortical neurons, CIP, a small peptide, inhibited Cdk5/p25 activity and restored insulin secretion. The same results were detected in co-infection of dominant negative Cdk5 (DNCdk5) with p25. CIP also reduced beta cells apoptosis induced by Cdk5/p25. These studies indicate that Cdk5/p25 hyperactivation deregulates insulin secretion and induces cell death in pancreatic beta cells and suggests that CIP may serve as a therapeutic agent for type 2 diabetes.

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Contribution of Insulin Resistance in Pathogenesis of Alzheimer Disease

Erol¹

2013

Metabolic Syndrome and Neurological Disorders

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Overexpression of p35 in Min6 pancreatic beta cells induces a stressed neuron-like apoptosis

Cited by 18 publications

References 32 publications

TFP5, a Peptide Derived from p35, a Cdk5 Neuronal Activator, Rescues Cortical Neurons from Glucose Toxicity

TFP5, a Peptide Derived from p35, a Cdk5 Neuronal Activator, Rescues Cortical Neurons from Glucose Toxicity

Cdk5 Inhibitory Peptide (CIP) Inhibits Cdk5/p25 Activity Induced by High Glucose in Pancreatic Beta Cells and Recovers Insulin Secretion from p25 Damage

Contribution of Insulin Resistance in Pathogenesis of Alzheimer Disease

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