Yasuomi Urano

Doshisha University, Kioto, Kyōto, Japan

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Publications (24)113.24 Total impact

  • Noriko Noguchi · Yasuomi Urano · Wakako Takabe · Yoshiro Saito ·
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    ABSTRACT: 24(S)-hydroxycholesterol (24S-OHC), which is enzymatically produced in the brain, has been known to play an important role in maintaining cholesterol homeostasis in the brain and has been proposed as a possible biomarker of neurodegenerative disease. Recent studies have revealed diverse functions of 24S-OHC and gained increased attention. For example, 24S-OHC at sub-lethal concentrations has been found to induce adaptive response via activation of the liver X receptor signaling pathway, thereby protecting neuronal cells against subsequent oxidative stress. It has also been found that physiological concentrations of 24S-OHC suppress amyloid-β production via down-regulation of amyloid precursor protein trafficking in neuronal cells. On the other hand, high concentrations of 24S-OHC have been found to induce a type of non-apoptotic programmed cell death in neuronal cells expressing little caspase-8. Since neuronal cell death induced by 24S-OHC has been found to proceed by a unique mechanism which is different from but in some ways similar to necroptosis-necroptosis being a type of programmed necrosis induced by tumor necrosis factor α-neuronal cell death induced by 24S-OHC has been called "necroptosis-like" cell death. 24S-OHC-induced cell death is dependent on formation of 24S-OHC esters but not on oxidative stress. This review article discusses newly reported aspects of 24S-OHC in neuronal cell death and sheds light on the possible importance of controlling 24S-OHC levels in the brain for preventing neurodegenerative disease. Copyright © 2015. Published by Elsevier Inc.
    Free Radical Biology and Medicine 07/2015; 87. DOI:10.1016/j.freeradbiomed.2015.06.036 · 5.74 Impact Factor
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    ABSTRACT: Lysophosphatidylcholine (LPC) and oxysterols which are major components in oxidized low-density lipoprotein (oxLDL) have been shown to possess an opposite effect on the expression of sterol regulatory element-binding protein-2 (SREBP-2) target genes in endothelial cells. In the present study, we aimed at elucidating the mechanisms of activation of SREBP-2 by LPC and evaluating the effects of LPC and 25-hydroxycholesterol (25-HC) on the release of inflammatory cytokines. Human umbilical vein endothelial cells (HUVEC) were treated with LPC or oxysterols including 25-HC. LPC activated SREBP-2 within 15 min, resulting in induction of expression of SREBP-2 target genes which were involved in intracellular cholesterol homeostasis. The rapid activation of SREBP-2 was caused by enhanced efflux of intracellular cholesterol, which was evaluated using (14)C-acetate. The LPC-induced activation of SREBP-2 was inhibited by addition of 25-HC. In contrast, both LPC and 25-HC increased release of interleukin-6 (IL-6) and IL-8, respectively and additively. In conclusion, LPC activated SREBP-2 via enhancement of cholesterol efflux, which was suppressed by 25-HC. The release of inflammatory cytokines such as IL-6 and IL-8 in endothelial cells was SREBP-2-independent. LPC and 25-HC may act competitively in cholesterol homeostasis but additively in inflammatory cytokine release. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.
    Journal of Biochemistry 05/2015; 158(4). DOI:10.1093/jb/mvv044 · 2.58 Impact Factor
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    ABSTRACT: 24(S)-hydroxycholesterol (24S-OHC), which is enzymatically produced in the brain, is known to play an important role in maintaining brain cholesterol homeostasis. We have previously reported that 24S-OHC induces a type of non-apoptotic programmed necrosis in neuronal cells expressing little caspase-8. Necroptosis has been characterized as a type of programmed necrosis in which activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) is involved in the signaling pathway. In the present study, we investigated the involvement of these three proteins in 24S-OHC-induced cell death. We found that RIPK1 but neither RIPK3 nor MLKL was expressed in human neuroblastoma SH-SY5Y cells, while all three proteins were expressed in human T lymphoma caspase-8-deficient Jurkat (Jurkat(Cas8-/-)) cells. In Jurkat(Cas8-/-) cells, tumor necrosis factor α (TNFα)-induced cell death was significantly suppressed by treatment with respective inhibitors of RIPK1, RIPK3, and MLKL. In contrast, only RIPK1 inhibitor showed significant suppression of 24S-OHC-induced cell death, and even this was less prominent than was observed in TNFα-induced cell death. In Jurkat(Cas8-/-) cells, knockdown of either RIPK1 or RIPK3 caused moderate but significant suppression of 24S-OHC-induced cell death, but no such effect was observed as a result of knockdown of MLKL. Collectively, these results suggest that, for both SH-SY5Y cells and Jurkat(Cas8-/-) cells, 24S-OHC-induced cell death is dependent on RIPK1 but not on MLKL. We therefore conclude that, in the absence of caspase-8 activity, 24S-OHC induces a necroptosis-like cell death which is RIPK1-dependent but MLKL-independent. Copyright © 2015. Published by Elsevier Inc.
    Steroids 02/2015; 99(Pt B). DOI:10.1016/j.steroids.2015.02.007 · 2.64 Impact Factor
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    ABSTRACT: According to the amyloid hypothesis, amyloid β accumulates in brains with Alzheimer's disease (AD) and triggers cell death and memory deficit. Previously, we developed a rice Aβ vaccine expressing Aβ, which reduced brain Aβ levels in the Tg2576 mouse model of familial AD. We used senescence-accelerated SAMP8 mice as a model of sporadic AD and investigated the relationship between Aβ and oxidative stress. Insoluble Aβ and 4-hydroxynonenal (4-HNE) levels tended to be reduced in SAMP8 mice-fed the rice Aβ vaccine. We attempted to clarify the relationship between oxidative stress and Aβ in vitro. Addition of Aβ peptide to the culture medium resulted in an increase in 4-HNE levels in SH-SY5Y cells. Tg2576 mice, which express large amounts of Aβ in their brain, also exhibited increased 4-HNE levels; this increase was inhibited by the Aβ vaccine. These results indicate that Aβ induces oxidative stress in cultured cells and in the mouse brain.
    Bioscience Biotechnology and Biochemistry 01/2015; 79(6):1-7. DOI:10.1080/09168451.2014.1002449 · 1.06 Impact Factor
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    Noriko Noguchi · Yoshiro Saito · Yasuomi Urano ·
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    ABSTRACT: 24(S)-hydroxycholesterol (24S-OHC) which is enzymatically produced in the brain plays important physiological roles in maintaining brain cholesterol homeostasis. We found that 24S-OHC at sub-lethal concentrations down-regulated amyloid precursor protein (APP) trafficking via enhancement of the complex formation of APP with up-regulated glucose-regulated protein 78, an endoplasmic reticulum chaperone. In accordance with this mechanism, 24S-OHC suppressed amyloid-β production in human neuroblastoma SH-SY5Y cells. Furthermore, 24S-OHC at sub-lethal concentrations induced adaptive responses via transcriptional activation of the liver X receptor signaling pathway, thereby protecting neuronal cells against the forthcoming oxidative stress induced by 7-ketocholesterol. On the other hand, we found that high concentrations of 24S-OHC induced apoptosis in T-lymphoma Jurkat cells which endogenously expressed caspase-8, and induced necroptosis -a form of programmed necrosis- in neuronal SH-SY5Y cells which expressed no caspase-8. In this article, we show the diverse functions of 24S-OHC and consider the possible importance of controlling 24S-OHC levels in the brain for preventing neurodegenerative diseases.
    Biochemical and Biophysical Research Communications 04/2014; 446(3). DOI:10.1016/j.bbrc.2014.02.010 · 2.30 Impact Factor
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    K Yamanaka · Y Urano · W Takabe · Y Saito · N Noguchi ·
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    ABSTRACT: 24(S)-hydroxycholesterol (24S-OHC), which is enzymatically produced in the brain, has an important role in maintaining brain cholesterol homeostasis. We have previously reported that 24S-OHC induces necroptosis in human neuroblastoma SH-SY5Y cells. In the present study, we investigated the mechanisms by which 24S-OHC-induced cell death occurs. We found that lipid droplets formed at the early stages in the treatment of SH-SY5Y cells with 24S-OHC. These lipid droplets could be almost completely eliminated by treatment with a specific inhibitor or by siRNA knockdown of acyl-CoA:cholesterol acyltransferase 1 (ACAT1). In association with disappearance of lipid droplets, cell viability was recovered by treatment with the inhibitor or siRNA for ACAT1. Using gas chromatography-mass spectrometry, we confirmed that 24S-OHC-treated cells exhibited accumulation of 24S-OHC esters but not of cholesteryl esters and confirmed that accumulation of 24S-OHC esters was reduced when ACAT1 was inhibited. 24S-OHC induced apoptosis in T-lymphoma Jurkat cells, which endogenously expressed caspase-8, but did not induce apoptosis in SH-SY5Y cells, which expressed no caspase-8. In Jurkat cells treated with the pan-caspase inhibitor ZVAD and in caspase-8-deficient Jurkat cells, 24S-OHC was found to induce caspase-independent cell death, and this was partially but significantly inhibited by Necrostatin-1. Similarly, knockdown of receptor-interacting protein kinase 3, which is one of the essential kinases for necroptosis, significantly suppressed 24S-OHC-induced cell death in Jurkat cells treated with ZVAD. These results suggest that 24S-OHC can induce apoptosis or necroptosis, which of the two is induced being determined by caspase activity. Regardless of the presence or absence of ZVAD, 24S-OHC treatment induced the formation of lipid droplets and cell death in Jurkat cells, and this was suppressed by treatment with ACAT1 inhibitor. Collectively, these results suggest that it is ACAT1-catalyzed 24S-OHC esterification and the resulting lipid droplet formation that is the initial key event which is responsible for 24S-OHC-induced cell death.
    Cell Death & Disease 01/2014; 5(1):e990. DOI:10.1038/cddis.2013.524 · 5.01 Impact Factor
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    ABSTRACT: Lipid peroxidation products have been known to induce cellular adaptive responses and enhance tolerance against subsequent oxidative stress through up-regulation of antioxidant compounds and enzymes. 24S-hydroxycholesterol (24SOHC) which is endogenously produced oxysterol in the brain plays an important role in maintaining brain cholesterol homeostasis. In this study, we evaluated adaptive responses induced by brain-specific oxysterol 24SOHC in human neuroblastoma SH-SY5Y cells. Cells treated with 24SOHC at sub-lethal concentrations showed significant reduction in cell death induced by subsequent treatment with 7-ketocholesterol (7KC) in both undifferentiated and retinoic acid-differentiated SH-SY5Y cells. These adaptive responses were also induced by other oxysterols such as 25-hydroxycholesterol and 27-hydroxycholesterol which are known to be ligands of liver X receptor (LXR). Co-treatment of 24SOHC with 9-cis retinoic acid, a retinoid X receptor ligand, enhanced the adaptive responses. Knockdown of LXRβ by siRNA diminished the adaptive responses induced by 24SOHC almost completely. The treatment with 24SOHC induced the expression of LXR target genes, such as ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1). The 24SOHC-induced adaptive responses were significantly attenuated by siRNA for ABCG1 but not by siRNA for ABCA1. Taken together, these results strongly suggest that 24SOHC at sub-lethal concentrations induces adaptive responses via transcriptional activation of LXR signaling pathway, thereby protecting neuronal cells from subsequent 7KC-induced cytotoxicity.
    12/2013; 2(1):28-35. DOI:10.1016/j.redox.2013.11.007
  • Yasuomi Urano · Sachika Ochiai · Noriko Noguchi ·
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    ABSTRACT: Cholesterol can be converted to 24S-hydroxycholesterol (24SOHC) by neuronal cholesterol 24-hydroxylase. In mouse models of Alzheimer's disease (AD), increasing 24SOHC levels reduced AD pathology. However, mechanisms underlying the effects of 24SOHC on amyloid-β (Aβ) production have remained unclear. Here we report that 24SOHC treatment reduces Aβ production and increases endoplasmic reticulum (ER)-resident immature amyloid precursor protein (APP) levels in human neuroblastoma SH-SY5Y cells and CHO cells stably expressing human APP. Treatment with 1-10 μM 24SOHC (equivalent to the concentrations detected in human brain homogenates) diminished Aβ production (IC50=4.6 μM for Aβ40) without affecting secretase activities. To evaluate the intracellular APP transport, we established an in vitro vesicle formation assay. We found that APP budding via COPII vesicles was diminished by 70% in 24SOHC-treated cells. The proteomics and immunoblotting analysis revealed that 24SOHC induced the expression of glucose-regulated protein 78 (GRP78), an ER chaperone, through unfolded protein response pathways, and enhanced the formation of the APP/GRP78 complex. Knockdown of GRP78 diminished the inhibitory effects of 24SOHC on Aβ production. These results suggest that 24SOHC down-regulates APP trafficking via enhancement of the complex formation of APP with up-regulated GRP78 in the ER, resulting in suppression of Aβ production.-Urano, Y., Ochiai, S., Noguchi, N. Suppression of amyloid-β production by 24S-hydroxycholesterovia inhibition of intracellular amyloid precursor protein trafficking.
    The FASEB Journal 07/2013; 27(10). DOI:10.1096/fj.13-231456 · 5.04 Impact Factor
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    ABSTRACT: Several lines of evidence suggest that aberrant Notch signaling contributes to the development of several types of cancer. Activation of Notch receptor is executed through intramembrane proteolysis by γ-secretase, which is a multimeric membrane-embedded protease comprised of presenilin, nicastrin (NCT), anterior pharynx defective 1 and PEN-2. In this study, we report the neutralization of the γ-secretase activity by a novel monoclonal antibody A5226A against the extracellular domain of NCT, generated by using a recombinant budded baculovirus as an immunogen. This antibody recognized fully glycosylated mature NCT in the active γ-secretase complex on the cell surface, and inhibited the γ-secretase activity by competing with the substrate binding in vitro. Moreover, A5226A abolished the γ-secretase activity-dependent growth of cancer cells in a xenograft model. Our data provide compelling evidence that NCT is a molecular target for the mechanism-based inhibition of γ-secretase, and that targeting NCT might be a novel therapeutic strategy against cancer caused by aberrant γ-secretase activity and Notch signaling.
    Oncogene 07/2011; 31(6):787-98. DOI:10.1038/onc.2011.265 · 8.46 Impact Factor
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    ABSTRACT: 24(S)-Hydroxycholesterol (24S-OHC) produced by cholesterol 24-hydroxylase expressed mainly in neurons plays an important physiological role in the brain. Conversely, it has been reported that 24S-OHC possesses potent cytotoxicity. The molecular mechanisms of 24S-OHC-induced cell death have not yet been fully elucidated. In this study, using human neuroblastoma SH-SY5Y cells and primary cortical neuronal cells derived from rat embryo, we characterized the form of cell death induced by 24S-OHC. SH-SY5Y cells treated with 24S-OHC exhibited neither fragmentation of the nucleus nor caspase activation, which are the typical characteristics of apoptosis. 24S-OHC-treated cells showed necrosis-like morphological changes but did not induce ATP depletion, one of the features of necrosis. When cells were treated with necrostatin-1, an inhibitor of receptor-interacting serine/threonine kinase 1 (RIPK1) required for necroptosis, 24S-OHC-induced cell death was significantly suppressed. The knockdown of RIPK1 by transfection of small interfering RNA of RIPK1 effectively attenuated 24S-OHC-induced cell death. It was found that neither SH-SY5Y cells nor primary cortical neuronal cells expressed caspase-8, which was regulated for RIPK1-dependent apoptosis. Collectively, these results suggest that 24S-OHC induces neuronal cell death by necroptosis, a form of programmed necrosis.
    Journal of Biological Chemistry 05/2011; 286(28):24666-73. DOI:10.1074/jbc.M111.236273 · 4.57 Impact Factor

  • Free Radical Biology and Medicine 12/2010; 49. DOI:10.1016/j.freeradbiomed.2010.10.382 · 5.74 Impact Factor
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    ABSTRACT: 6-Hydroxydopamine (6-OHDA) is a neurotoxin that has been widely used to generate Parkinson's disease (PD) models. Increased oxidative stress is suggested to play an important role in 6-OHDA-induced cell death. Given the lessened susceptibility to oxidative stress exhibited by mice lacking p66shc, this study investigated the role of p66shc in the cytotoxicity of 6-OHDA. 6-OHDA induced cell death and p66shc phosphorylation at Ser36 in SH-SY5Y cells. Pre-treatment with the protein kinase C β (PKCβ) inhibitor hispidin suppressed 6-OHDA-induced p66shc phosphorylation. Elimination of H(2)O(2) by catalase reduced cell death and p66shc phosphorylation induced by 6-OHDA. Cells deficient in p66shc were more resistant to 6-OHDA-induced cell death than wild-type cells. Furthermore, reconstitution of wild-type p66shc, but not the S36A mutant, in p66shc-deficient cells increased susceptibility to 6-OHDA. These results indicate that H(2)O(2) derived from 6-OHDA is an important mediator of cell death and p66shc phosphorylation induced by 6-OHDA and that p66shc phosphorylation at Ser36 is indispensable for the cytotoxicity of 6-OHDA.
    Free Radical Research 11/2010; 45(3):342-50. DOI:10.3109/10715762.2010.532496 · 2.98 Impact Factor
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    ABSTRACT: FDPS (farnesyl diphosphate synthase) catalyses the formation of farnesyl diphosphate, a key intermediate in the synthesis of cholesterol and isoprenylated cellular metabolites. FDPS is also the molecular target of nitrogen-containing bisphosphonates, which are used as bone-antiresorptive drugs in various disorders. In the present study, we characterized the sterol-response element and NF-Y (nuclear factor Y)-binding site in the human FDPS promoter. Using a luciferase assay, electrophoretic mobility-shift assay and chromatin immunoprecipitation assay, we demonstrated that these elements are responsible for the transcription of the FDPS gene, and that its transcriptional activation is mediated by SREBP-2 (sterol-regulatory-element-binding protein 2) and NF-Y. We also investigated whether sterol-mediated FDPS expression is involved in the cell proliferation induced by zoledronic acid, an FDPS inhibitor. We show that the SREBP-2- and NF-Y-mediated regulation of FDPS gene transcription modulates cell proliferation. These results suggest that SREBP-2 and NF-Y are required to trigger cell proliferation through the induction of FDPS expression and that the pharmacological action of zoledronic acid is involved in this pathway.
    Biochemical Journal 05/2010; 429(2):347-57. DOI:10.1042/BJ20091511 · 4.40 Impact Factor
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    ABSTRACT: Gamma-secretase is a membrane protein complex that catalyzes intramembrane proteolysis of a variety of substrates including the amyloid beta precursor protein of Alzheimer disease. Nicastrin (NCT), a single-pass membrane glycoprotein that harbors a large extracellular domain, is an essential component of the gamma-secretase complex. Here we report that overexpression of a single chain variable fragment (scFv) against NCT as an intrabody suppressed the gamma-secretase activity. Biochemical analyses revealed that the scFv disrupted the proper folding and the appropriate glycosyl maturation of the endogenous NCT, which are required for the stability of the gamma-secretase complex and the intrinsic proteolytic activity, respectively, implicating the dual role of NCT in the gamma-secretase complex. Our results also highlight the importance of the calnexin cycle in the functional maturation of the gamma-secretase complex. The engineered intrabodies may serve as rationally designed, molecular targeting tools for the discovery of novel actions of the membrane proteins.
    Journal of Biological Chemistry 09/2009; 284(41):27838-47. DOI:10.1074/jbc.M109.055061 · 4.57 Impact Factor

  • Alzheimer's and Dementia 07/2009; 5(4). DOI:10.1016/j.jalz.2009.04.504 · 12.41 Impact Factor

  • Alzheimer's and Dementia 07/2009; 5(4). DOI:10.1016/j.jalz.2009.05.225 · 12.41 Impact Factor
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    Ta-Yuan Chang · Bo-Liang Li · Catherine C Y Chang · Yasuomi Urano ·
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    ABSTRACT: The enzymes acyl-coenzyme A (CoA):cholesterol acyltransferases (ACATs) are membrane-bound proteins that utilize long-chain fatty acyl-CoA and cholesterol as substrates to form cholesteryl esters. In mammals, two isoenzymes, ACAT1 and ACAT2, encoded by two different genes, exist. ACATs play important roles in cellular cholesterol homeostasis in various tissues. This chapter summarizes the current knowledge on ACAT-related research in two areas: 1) ACAT genes and proteins and 2) ACAT enzymes as drug targets for atherosclerosis and for Alzheimer's disease.
    AJP Endocrinology and Metabolism 02/2009; 297(1):E1-9. DOI:10.1152/ajpendo.90926.2008 · 3.79 Impact Factor
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    ABSTRACT: Mammalian cells acquire cholesterol mainly from LDL. LDL enter the endosomes, allowing cholesteryl esters to be hydrolyzed by acid lipase. The hydrolyzed cholesterol (LDL-CHOL) enters the Niemann-Pick type C1 (NPC1)-containing endosomal compartment en route to various destinations. Whether the Golgi is involved in LDL-CHOL transport downstream of the NPC1 compartment has not been demonstrated. Using subcellular fractionation and immunoadsorption to enrich for specific membrane fractions, here we show that, when parental Chinese hamster ovary (CHO) cells are briefly exposed to (3)H-cholesteryl linoleate (CL) labeled-LDL, newly liberated (3)H-LDL-CHOL appears in membranes rich in trans-Golgi network (TGN) long before it becomes available for re-esterification at the endoplasmic reticulum (ER) or for efflux at the plasma membrane. In mutant cells lacking NPC1, the appearance of newly liberated (3)H-LDL-CHOL in the TGN-rich fractions is much reduced. We next report a reconstituted transport system that recapitulates the transport of LDL-CHOL to the TGN and to the ER. The transport system requires ATP and cytosolic factors and depends on functionality of NPC1. We demonstrate that knockdown by RNAi of 3 TGN-specific SNAREs (VAMP4, syntaxin 6, and syntaxin 16) reduces >/=50% of the LDL-CHOL transport in intact cells and in vitro. These results show that vesicular trafficking is involved in transporting a significant portion of LDL-CHOL from the NPC1-containing endosomal compartment to the TGN before its arrival at the ER.
    Proceedings of the National Academy of Sciences 10/2008; 105(43):16513-8. DOI:10.1073/pnas.0807450105 · 9.67 Impact Factor
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    Patrick C Reid · Yasuomi Urano · Tatsuhiko Kodama · Takao Hamakubo ·
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    ABSTRACT: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and the most prevalent form of dementia worldwide. AD is characterized pathologically by amyloid-? plaques, neurofibrillary tangles and neuronal loss, and clinically by a progressive loss of cognitive abilities. At present, the fundamental molecular mechanisms underlying the disease are unclear and no treatment for AD is known. Epidemiological evidence continues to mount linking vascular diseases, such as hypertension and diabetes, and hypercholesterolaemia with an increased risk for developing AD. A growing amount of evidence suggests a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques in AD development. Cholesterol and statins clearly modulate ?-amyloid precursor protein (?APP) processing in cell culture and animal models. Statins not only reduce endogenous cholesterol synthesis but also exert other various pleiotrophic effects, such as the reduction in protein isoprenylation. Through these effects statins modulate a variety of cellular functions involving both cholesterol (and membrane rafts) and isoprenylation. Although clearly other factors, such as vascular inflammation, oxidative stress and genetic factors, are intimately linked with the progression of AD, this review focuses on the present research findings describing the effect of cholesterol, membrane rafts and isoprenylation in regulating ?APP processing and in particular ?-secretase complex assembly and function and AD progression, along with consideration for the potential role statins may play in modulating these events.
    Journal of Cellular and Molecular Medicine 05/2007; 11(3):383-92. DOI:10.1111/j.1582-4934.2007.00054.x · 4.01 Impact Factor
  • Article: P3-412

Publication Stats

787 Citations
113.24 Total Impact Points


  • 2010-2015
    • Doshisha University
      • Department of Medical Life Systems
      Kioto, Kyōto, Japan
  • 2009
    • National Institute of Advanced Industrial Science and Technology
      Tsukuba, Ibaraki, Japan
  • 2007-2009
    • Dartmouth Medical School
      • Department of Biochemistry
      Hanover, New Hampshire, United States
  • 2003-2009
    • The University of Tokyo
      • Research Center for Advanced Science and Technology
      白山, Tōkyō, Japan