Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: investigation of P-glycoprotein as a novel therapeutic target for Alzheimer's disease

Abuznait, Alaa H.; Cain, Courtney; Ingram, Drury; Burk, David H.; Kaddoumi, Amal

doi:10.1111/j.2042-7158.2011.01309.x

Cited by 68 publications

(65 citation statements)

References 35 publications

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“…P-gp is expressed abundantly on the canalicular side of hepatocytes, and Ab 40 is a P-gp substrate (Lam et al, 2001). P-gp at the apical side of BBB has been shown to play a substantial role in controlling Ab levels in the brain by enhancing its removal from brain to blood and by limiting Ab access to the brain (Cirrito et al, 2005;Kuhnke et al, 2007;Abuznait et al, 2011). To study the role of P-gp in the canalicular excretion of Ab 40 , two potent P-gp inhibitors, verapamil and valspodar, were used.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Investigation of Amyloid-β Hepatobiliary Disposition in Sandwich-Cultured Primary Rat Hepatocytes

Mohamed

Kaddoumi

2013

Drug Metab Dispos

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Failure in amyloid-b (Ab) systemic clearance across the liver has been suggested to play a role in Ab brain accumulation and thus to contribute largely to the pathology of Alzheimer's disease (AD). The purpose of this study was to characterize in vitro the transport mechanisms of Ab 40 across the liver using sandwich-cultured primary rat hepatocytes (SCHs) and to determine its biliary clearance (CL bile ) and biliary excretion index (BEI%). I-Ab 40 biliary excretion was inducible and increased BEI% by 26% after rifampicin pretreatment. In conclusion, our findings demonstrated that besides LRP1, P-gp and, to a lesser extent, RAGE are involved in 125 I-Ab 40 hepatobiliary disposition and support the use of enhancement of Ab hepatic clearance via LRP1 and P-gp induction as a novel therapeutic approach for the prevention and treatment of AD.

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Section: Discussionmentioning

confidence: 99%

In Vitro Investigation of Amyloid-β Hepatobiliary Disposition in Sandwich-Cultured Primary Rat Hepatocytes

Mohamed

Kaddoumi

2013

Drug Metab Dispos

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“…In vitro accumulation studies using the human colon adenocarcinoma cell line LS-180, which endogenously expresses ABCB1 and pregnane-X-receptor (PXR), 67 demonstrated that the cotreatment of Aβ 40 with the ABCB1 inhibitor verapamil significantly increased Aβ 40 cellular accumulation, confirming its role in limiting Aβ cellular entry. 38 Moreover, utilizing in vivo brain efflux index (BEI%) studies conducted on C57BL/6 mice provided further evidence to the important role of ABCB1 in the clearance of 125 I-Aβ 40 from the brain where inhibition studies with valspodar (ABCB1 inhibitor) caused 18% reduction in 125 I-Aβ 40 clearance (P < 0.05).…”

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confidence: 99%

“…68 In addition, in vitro and in vivo up-regulation of ABCB1 by different ABCB1 inducers significantly modulated Aβ levels. 38,65 The in vitro treatment of LS-180 cells with rifampicin, caffeine, verapamil, hyperforin, and β-estradiol, and to a lesser extent pentylenetetrazole and dexamethasone, resulted in significant decrease in the intracellular accumulation of Aβ 40 when compared to control as a result of ABCB1 up-regulation. 38 Furthermore, in vivo BEI% studies conducted on C57BL/6 mice treated with rifampicin or caffeine significantly enhanced Aβ 40 clearance by more than 20% when compared to control vehicle treated mice.…”

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confidence: 99%

Role of ABC Transporters in the Pathogenesis of Alzheimer’s Disease

Abuznait

Kaddoumi

2012

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of age-related dementia that begins with memory loss and progresses to include severe cognitive impairment. A major pathological hallmark of AD is the accumulation of beta amyloid peptide (Aβ) in senile plaques in the brain of AD patients. The exact mechanism by which AD takes place remains unknown. However, an increasing number of studies suggests that ATP-binding cassette (ABC) transporters, which are localized on the surface of brain endothelial cells of the bloodbrain barrier (BBB) and brain parenchyma, may contribute to the pathogenesis of AD. Recent studies have unraveled important roles of ABC transporters including ABCB1 (P-glycoprotein, P-gp), ABCG2 (breast cancer resistant protein, BCRP), ABCC1 (multidrug resistance protein 1, MRP1), and the cholesterol transporter ABCA1 in the pathogenesis of AD and Aβ peptides deposition inside the brain. Therefore, understanding the mechanisms by which these transporters contribute to Aβ deposition in the brain is important for the development of new therapeutic strategies against AD. This review summarizes and highlights the accumulating evidence in the literature which describe the role of altered function of various ABC transporters in the pathogenesis and progression of AD and the implications of modulating their functions for the treatment of AD. KEYWORDS: ABC transporters, Alzheimer's disease, blood-brain barrier, ABCA1, P-glycoprotein, MRP1, BCRP A lzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of age-related dementia that begins with memory loss and progresses to include severe cognitive impairment.1 The pathogenesis of AD is complex, and involves molecular, genetic, cellular, and physiological alterations to the brain and blood-brain barrier (BBB) that are still not completely understood.2,3 The prevalence of AD is going up rapidly worldwide, with about 30 million people suffering from this disease nowadays, and it has an increasing socioeconomic impact. 4 Despite the huge demand for treatments, existing drugs have limited or no efficacy for AD. 5,6 AD is characterized by a significant loss of neurons and atrophy of the hippocampus and cerebral cortex.7 It begins as mild short-term memory disturbances and ends in total loss of cognition and executive functions.8−10 The neuropathology of AD is characterized by two pathogenic hallmarks: the intraneuronal neurofibrillary tangle (NFT) and the extracellular amyloid plaque. 11,12 NFTs are largely composed of hyperphosphorylated fibrillar forms of a protein called microtubule associated protein tau which accumulates in the entorhinal cortex and the pyramidal neurons of the CA1 region of the hippocampus and subiculum.7 The well-known amyloid cascade hypothesis suggests that AD is precipitated by the accumulation of amyloid plaques that are mainly composed of fibrils of peptides collectively known as beta amyloid (Aβ) which are produced by the sequential cleavage of am...

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“…mediated) in the cell membranes with transport of cholesterol to HDL and LDL [138] [139]. In AD, upregulation of Pgp is involved in the rapid clearance of amyloid beta from the brain with implications for Pgp as a therapeutic target for amyloid beta and xenobiotic clearance in the brain [143] [144]. Upregulation of Pgp activity in the liver is involved in PXR protein levels with implications of diet on PPAR-Sirt1/PXR interactions [145] [146] involved in regulation of Pgp mediated xenobiotic clearance in chronic diseases such as the kidney.…”

Section: Endocrine Disruptors As Risk Factors For Obesity and Chronicmentioning

confidence: 99%

Induction of NAFLD with Increased Risk of Obesity and Chronic Diseases in Developed Countries

Martins¹

2014

OJEMD

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The susceptibility of individuals to obesity has been reported in many developed countries with predisposition of humans to obesity associated with high calorie diets and unhealthy lifestyles. Obesity may closely be involved in cell suicide in various organ diseases with the importance of accelerated aging that requires early intervention with drug therapy to prevent diseases such as non alcoholic fatty liver disease (NAFLD) that has increased in children and reached to approx. 40% of the global population. Obesity is induced by various diets and lifestyle factors such as stress, anxiety and depression which are important to consider with the global increase in obesity and are possibly linked to the rise in individuals with brain disorders that involve neurodegeneration. Xenobiotics such as the endocrine disruptor chemicals that have increased in the environment in various developed countries lead to various chronic endocrine diseases as populations divert towards unhealthy diets and lifestyles with induction of NAFLD and obesity. The amount and nature of food intake that improves and increases liver lipid and xenobiotic metabolism in obese individuals have become important to decrease the risk for increased adiposity in man. High fibre or protein diets that contain leucine may improve liver glucose, lipid and xenobiotic metabolism and require further investigation with xenobiotics such as endocrine disruptors involved in appetite dysregulation and metabolic disorders in developed countries. The use of anti-obese drugs that reduce food intake and improve hypercholesterolemia and cardiovascular disease has been assessed in obesity with drug therapy closely involved either in the prevention or induction of NAFLD and obesity in man.

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Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: investigation of P-glycoprotein as a novel therapeutic target for Alzheimer's disease

Cited by 68 publications

References 35 publications

In Vitro Investigation of Amyloid-β Hepatobiliary Disposition in Sandwich-Cultured Primary Rat Hepatocytes

In Vitro Investigation of Amyloid-β Hepatobiliary Disposition in Sandwich-Cultured Primary Rat Hepatocytes

Role of ABC Transporters in the Pathogenesis of Alzheimer’s Disease

Induction of NAFLD with Increased Risk of Obesity and Chronic Diseases in Developed Countries

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