ABCA1, a member of the ATP-binding cassette transporter family, promotes the efflux of cholesterol and phospholipids from intracellular compartments to extracellular cholesterol acceptors.1) Mutations in the ABCA1 gene result in high-density lipoprotein (HDL) deficiency syndromes, such as Tangier disease, which is characterized by low levels of HDL cholesterol and apolipoprotein A-I (apoA-I) and an increased risk of cardiovascular disease.2,3) ABCA1 also plays an important role in the central nervous system (CNS). Apolipoprotein E (apoE) is one of the major apolipoproteins in CNS, which interacts with ABCA1 4) to remove cholesterol from cells and generates HDL particles in the cerebrospinal fluid.5) The lack of ABCA1 results in a reduction of apoE levels and lipidated apoE-containing lipoproteins in the brain of ABCA1 Ϫ / Ϫ mice.6) It has also been reported that decreased apoE levels and poorly lipidated apoE increase amyloid-b peptide (Ab), a major component of the senile plaque in Alzheimer disease (AD) brains, deposition in ABCA1 Ϫ / Ϫ mice crossed with the AD mouse model. 7) In contrast, overexpression of ABCA1 results in the reduction of Ab deposition through ABCA1-mediated generation of apoE containing lipoproteins in the AD mouse model 8) suggesting that modulation of ABCA1 expression could be a possible therapeutic strategy for AD.ABCA1 is ubiquitously expressed, the expression of which is transcriptionally regulated. The activation of liver X receptor (LXR) by oxysterols and the nonsteriodal synthetic LXR agonist T0901317 increases ABCA1 gene expression level. 9)ABCA1 is also regulated by peroxisome proliferator-activated receptors (PPARs) through their inductive effects on the expression of LXRa.10) Both of these types of receptor form heterodimers with retinoid X receptors (RXRs), 11) and LXR/RXR and PPARs/LXR heterodimers bind to a promoter sequence on the ABCA1 gene. 10,12) In mice models, the synthetic LXR agonist GW3965 increases the plasma HDL cholesterol level and inhibits the development of atherosclerosis, 13) and decrease Ab deposition in the AD mouse model. 14) Although ABCA1 plays an important role in the development of atherosclerosis and pathogenesis of AD, there are relatively few drugs that can upregulate ABCA1 expression. Thus, identification of upregulators of ABCA1 expression may lead to a therapeutic benefit for patients with cardiovascular disease and AD.Because of their simplicity and sensitivity, reporter gene assay systems are used for high-throughput screening (HTS) to identify new compounds for drug development. These strategies offer the advantages of speed, cost-effectiveness, genome coverage, and immediate biological relevance. In the present study, we have developed an HTS method of identifying ABCA1 upregulators, and screened 118 natural compounds using the developed cell-based assay. MATERIALS AND METHODS MaterialsHonokiol and rosiglitazone were purchased from LKT laboratories, Inc. (St. Paul, MN, U.S.A.) and Cayman Chemical (Ann Arbor, MI, U.S.A.), respectively. GW6471,...
BackgroundRecently, several lines of evidence have shown the aberrant expression of cell-cycle-related proteins and tumor suppressor proteins in vulnerable neurons of the Alzheimer's disease (AD) brain and transgenic mouse models of AD; these proteins are associated with various paradigms of neuronal death. It has been reported that ATBF1 induces cell cycle arrest associated with neuronal differentiation in the developing rat brain, and that gene is one of the candidate tumor suppressor genes for prostate and breast cancers in whose cells overexpressed ATBF1 induces cell cycle arrest. However, the involvement of ATBF1 in AD pathogenesis is as yet unknown.ResultsWe found that ATBF1 was up-regulated in the brains of 17-month-old Tg2576 mice compared with those of age-matched wild-type mice. Moreover, our in vitro studies showed that Aβ1-42 and DNA-damaging drugs, namely, etoposide and homocysteine, increased the expression ATBF1 level in primary rat cortical neurons, whereas the knockdown of ATBF1 in these neurons protected against neuronal death induced by Aβ1-42, etoposide, and homocysteine, indicating that ATBF1 mediates neuronal death in response to these substances. In addition, we found that ATBF1-mediated neuronal death is dependent on ataxia-telangiectasia mutated (ATM) because the blockage of ATM activity by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 function in neuronal death. Furthermore, Aβ1-42 phosphorylates ATM, and ATBF1 interacts with phosphorylated ATM.ConclusionsTo the best of our knowledge, this is the first report that Aβ1-42 and DNA-damaging drugs increased the ATBF1 expression level in primary rat cortical neurons; this increase, in turn, may activate ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM. ATBF1 may therefore be a suitable target for therapeutic intervention of AD.
Urinary cells can be an ideal source for generating hiPSCs and progenitors, as they are easily accessible, non-invasive, and universally available. We generated human induced pluripotent stem cells (hiPSCs) from the urinary cells of a healthy donor using a Sendai virus-based gene delivery method. The generated hiPSC line, KSCBi001-A, has a normal karyotype (46,XY). The pluripotency and capacity of multilineage differentiation were characterized by comparison with those of a human embryonic stem cell line. This cell line is registered and available from National Stem Cell Bank, Korea National Institute of Health.
We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts using a Sendai virus (SeV)-based gene delivery method. The generated hiPSC line, KSCBi002-A, has a normal karyotype (46,XY). The pluripotency and differentiation capacity were characterized by comparison with those of a human embryonic stem cell line. This cell line is registered and available from the National Stem Cell Bank, Korea National Institute of Health.
Amyloid-β (Aβ) peptide plays a major role in the pathogenesis of Alzheimer's disease (AD), and is generated by β- and γ-secretase-mediated proteolytic processing of amyloid-β protein precursor (AβPP). In the present study, we investigated the effect of 118 natural compounds on Aβ production in the medium of HEK293 cells stably expressing human AβPP695 (HEK293-AβPP) using Aβ42 sandwich ELISA to find natural compounds that can modulate Aβ production. We found that a coumarin derivative of citrus fruits, auraptene, increased Aβ production. Treatment of HEK293-AβPP cells and rat primary cortical neurons with auraptene significantly increased the secretion of Aβ40, Aβ42, and the Aβ42/40 ratio. However, auraptene did not change the protein levels of the AβPP processing enzymes, a disintegrin and metalloproteinases 10 (ADAM10, α-secretase), β-site AβPP cleaving enzyme-1 (BACE-1, β-secretase), and presenilin 1 (PS1, γ-secretase component). Auraptene increased the activity of γ-secretase but not that of α- and β-secretase. Furthermore, auraptene enhanced γ-secretase-mediated production of Aβ from AβPP or AβPP-C99, but not through α- and β-secretase. Auraptene also phosphorylated c-Jun N-terminal kinase (JNK), and pretreatment with the JNK inhibitor, SP600125, reduced auraptene-induced γ-secretase activity. Overall, our results suggest that auraptene-mediated activation of JNK may contribute to the production of Aβ by promoting γ-secretase activity.
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