Clinico-Pathologic Function of Cerebral ABC Transporters – Implications for the Pathogenesis of Alzheimers Disease

University of Rostock, Department of Neurology, Neurodegeneration Research Laboratory (NRL), Gehlsheimer Str. 20, 18147 Rostock, Germany.
Current Alzheimer Research (Impact Factor: 3.89). 09/2008; 5(4):396-405. DOI: 10.2174/156720508785132262
Source: PubMed


In recent years it has become evident that ABC transporters fulfill important barrier functions in normal organs and during disease processes. Most importantly, resistance to drugs in cancer cells led to intense oncological and pharmacological investigations in which researchers were able to highlight important pharmacological interactions of chemotherapeuticals with ABC transporter function. Recently, the development of neurodegenerative diseases and the maintenance of neuronal stem cells have been linked to the activity of ABC transporters. Here, we summarize findings from cell culture experiments, animal models and studies of patients with Alzheimer's disease. Furthermore, we discuss pharmacological interactions and computational methods for risk assessment.

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    • "At the molecular level, accumulation and aggregation of the amyloid-β (Aβ) peptides, leading to senile plaque formation, and hyperphosphorylation of the tau protein, resulting in neurofibrillary tangle generation, are the major features of AD pathology. Adenosine triphosphate (ATP)-binding cassette subfamily B member 1 gene (ABCB1; MIM# 171050) at locus 7q21.1 encodes P-glycoprotein (P-gp), an efflux transporter that is located at the luminal side of the cerebral endothelial cells at the blood–brain barrier (Pahnke et al. 2008). P-gp effectively prevents a number of structurally different drugs and toxicants from entering the brain and removes metabolic waste products from the brain; hence, P-gp has an essential role in neuroprotection and overall brain homeostasis (Wolf et al. 2012). "
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    ABSTRACT: To evaluate the association of ATP-binding cassette subfamily B member 1 (ABCB1) genetic variants with the susceptibility to Alzheimer's disease (AD), we genotyped the rs1128503 (C1236T), rs2032582 (G2677T/A), and rs1045642 (C3435T) polymorphisms in a case-control sample (234 AD patients, 225 controls). Single-marker analyses revealed a significant association solely for the rs1045642 polymorphism (C/C genotype carriers had increased risk for AD), which remains significant after correction for multiple testing. Haplotype analyses indicated three nominally significant associations which were lost after applying multiple test correction.
    Journal of Molecular Neuroscience 10/2014; 54(4). DOI:10.1007/s12031-014-0427-z · 2.34 Impact Factor
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    • "In a review article, Pahnke et al. (2008) stated that BCRP partially compensates for a loss in P-gp-mediated Aβ clearance in hAPP-overexpressing AD mouse models that are P-gp-deficient at the blood-brain barrier. However, these data appear to be unpublished , and thus, the details of this work are unclear. "
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    ABSTRACT: Alzheimer's disease (AD) is considered the "disease of the twenty-first century." With a 10-fold increase in global incidence over the past 100 years, AD is now reaching epidemic proportions and by all projections, AD patient numbers will continue to rise. Despite intense research efforts, AD remains a mystery and effective therapies are still unavailable. This represents an unmet need resulting in clinical, social, and economic problems. Over the last decade, a new AD research focus has emerged: ATP-binding cassette (ABC) transporters. In this article, we provide an overview of the ABC transporters ABCA1, ABCA2, P-glycoprotein (ABCB1), MRP1 (ABCC1), and BCRP (ABCG2), all of which are expressed in the brain and have been implicated in AD. We summarize recent findings on the role of these five transporters in AD, and discuss their potential to serve as therapeutic targets.
    Frontiers in Psychiatry 06/2012; 3(45):54. DOI:10.3389/fpsyt.2012.00054
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    • "Recently, ABC transporters have been discovered to exhibit important export functions for proteins involved in Alzheimer's disease [11], [12], with ABCC1 being of exceptional importance for the clearance of β-amyloid from the brain [13]. In addition to their role as crucial components of barriers that protect the brain from toxic substances, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (reviewed in [12], [14]), these molecules also are expressed on stem cells of various tissues, and were discovered in cancer cells. "
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    ABSTRACT: ATP-binding cassette (ABC) transporters are essential regulators of organismic homeostasis, and are particularly important in protecting the body from potentially harmful exogenous substances. Recently, an increasing number of in vitro observations have indicated a functional role of ABC transporters in the differentiation and maintenance of stem cells. Therefore, we sought to determine brain-related phenotypic changes in animals lacking the expression of distinct ABC transporters (ABCB1, ABCG2 or ABCC1). Analyzing adult neurogenesis in ABC transporter-deficient animals in vivo and neuronal stem/progenitor cells in vitro resulted in complex findings. In vivo, the differentiation of neuronal progenitors was hindered in ABC transporter-deficient mice (ABCB1(0/0)) as evidenced by lowered numbers of doublecortin(+) (-36%) and calretinin(+) (-37%) cells. In vitro, we confirmed that this finding is not connected to the functional loss of single neural stem/progenitor cells (NSPCs). Furthermore, assessment of activity, exploratory behavior, and anxiety levels revealed behavioral alterations in ABCB1(0/0) and ABCC1(0/0) mice, whereas ABCG2(0/0) mice were mostly unaffected. Our data show that single ABC transporter-deficiency does not necessarily impair neuronal progenitor homeostasis on the single NSPC level, as suggested by previous studies. However, loss of distinct ABC transporters impacts global brain homeostasis with far ranging consequences, leading to impaired neurogenic functions in vivo and even to distinct behavioral phenotypes. In addition to the known role of ABC transporters in proteopathies such as Parkinson's disease and Alzheimer's disease, our data highlight the importance of understanding the general function of ABC transporters for the brain's homeostasis and the regeneration potential.
    PLoS ONE 04/2012; 7(4):e35613. DOI:10.1371/journal.pone.0035613 · 3.23 Impact Factor
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