Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer's Disease

Qosa, Hisham; Abuznait, Alaa H.; Hill, Ronald A.; Kaddoumi, Amal

doi:10.3233/jad-2012-120319

Cited by 140 publications

(157 citation statements)

References 51 publications

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“…65 These findings support the validity of increasing Aβ clearance via ABCB1 up-regulation as a therapeutic approach to slowing or halting the progression of AD.…”

supporting

confidence: 66%

“…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.…”

mentioning

confidence: 99%

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

Abuznait

Kaddoumi

2012

ACS Chem. Neurosci.

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111

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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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“…65 These findings support the validity of increasing Aβ clearance via ABCB1 up-regulation as a therapeutic approach to slowing or halting the progression of AD.…”

supporting

confidence: 66%

mentioning

confidence: 99%

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

Abuznait

Kaddoumi

2012

ACS Chem. Neurosci.

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111

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“…In addition, dissolving the vascular deposits could also lead to disruption of the vessel wall, increasing the chance of hemorrhages. The clearance of soluble Aβ could be stimulated by the widely used drugs caffeine and rifampicin, as these drugs both upregulate the blood brain barrier transporter P-glycoprotein, and rifampicin also upregulates LRP1 in wild-type mice (Qosa et al, 2012). As the proteolytic degradation of soluble Aβ is stimulated by ApoE, Cramer and colleagues hypothesized that enhancement of ApoE expression with the retinoid X receptor agonist bextarotene could promote Aβ clearance and microglial phagocytosis.…”

Section: Potential Therapies For Hchwa-dmentioning

confidence: 99%

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Kamp

Moursel²,

Haan³

et al. 2014

Reviews in the Neurosciences

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Hereditary cerebral hemorrhage with amyloidosis – Dutch type is an autosomal dominant hereditary disease caused by a point mutation in the amyloid precursor protein gene on chromosome 21. The mutation causes an amino acid substitution at codon 693 (E22Q), the ‘Dutch mutation’. Amyloid β, the product after cleavage of the amyloid precursor protein, is secreted into the extracellular space. The Dutch mutation leads to altered amyloid β cleavage and secretion, enhanced aggregation properties, higher proteolysis resistance, lowered brain efflux transporter affinity, and enhanced cell surfaces binding. All these result in amyloid β accumulation in cerebral vessel walls, causing cell death and vessel wall integrity loss, making cerebral vessel walls in hereditary cerebral hemorrhage with amyloidosis-Dutch type more prone to rupture and obstruction, leading to hemorrhages and infarcts. Studying the effects of altered amyloid β metabolism due to mutations like the ‘Dutch’ provides us with a better understanding of amyloid β toxicity, also in other amyloid β diseases like sporadic cerebral amyloid angiopathy and Alzheimer’s disease.

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“…One of the clearance pathways of amyloid-β is transport across the BBB via efflux transporters. Several BBB transporters have been implicated in Aβ exchange between brain parenchyma and the circulation [5][6][7][8][9][10][11][12]. Deficiency of either of the two major efflux pumps, ABCB1 and ABCG2, involved in Aβ trafficking across the BBB, results in increased accumulation of peripherallyinjected Aβ in the brain [13].…”

mentioning

confidence: 99%

“…ATP-binding cassette (ABC) transporters, which are localized on the surface of brain endothelial cells of the BBB and brain parenchyma, affect Aβ transport (flux) across the BBB contributing to the pathogenesis of Alzheimer's disease (AD) [5][6][7][8][9][10][11][12]. One of the clearance pathways of amyloid-β is transport across the BBB via efflux transporters.…”

mentioning

confidence: 99%