Inhibition of Alzheimer's Beta-Amyloid Fibril Formation

Summary

Principal Investigator: Duy Hua
Abstract: Alzheimer's disease (AD) is a progressive and irreversible brain disorder with no known cure. A small protein, amyloid beta peptide (Abeta) containing 39-43 amino acids, is widely considered a culprit for the disease. Recent evidence indicates that soluble oligomers of Abeta may represent the primary toxic species of amyloid in AD. It is accepted that newly produced Abeta is monomeric, soluble and non-toxic, adopting random coil/alpha-helix mixture structures under normal physiological conditions. In AD, Abeta undergoes conformational changes from random coil/alpha-helix to beta-sheet structure, resulting in oligomerization and precipitation. In search of a compound that blocks this conformational change, we discovered that a class of tricyclic pyrones (TP), especially CP2 (code name), prevents the death of human neuroblastoma MC65 cells related to intracellular accumulation of Abeta-containing metabolites. CP2 inhibits the aggregation of Abeta 1- 40 and Abeta1-42 peptides, blocks Abeta1-40 and Abeta1-42 beta-sheet formation, and binds to Abeta peptides in vitro. CP2 also penetrated blood-brain barrier in mice. These exciting results suggest that CP2 may potentially serve as a drug to treat AD. We propose the following specific aims: (1) Studies of the structural changes and aggregation states of Abeta40 and Abeta42 in the presence of CP2 and analogs;(2) Identification of the mechanism by which CP2 blocks beta-sheet formation and aggregation of Abeta40 and Abeta42;(3) Syntheses of a small library of TP, new analogs of CP2 containing functional groups at C9, C11 and C14;(4) Studies of the in vitro bioactivities of CP2 analogs in cell cultures;and (5) Studies of the in vivo pharmacological effect of CP2 analogs with 3xTg-AD APP mice. The ultimate goal of this proposal are to identify a lead compound that is able to block the formation of Ab lesions in animal model, which may lead to drugs for the treatment of AD. CP2 and its analogs should have great potential in AD drug development. Relevance: Oligomerization of amyloid beta-peptide has been shown to be a major feature of the pathogenesis of AD. Monomeric Abeta is produced during normal metabolism and appears to have no toxic effects on neurons. However, soluble oligomeric Abeta showed high neuronal toxicity. Inhibition of the formation of these toxic soluble Abeta oligomers would provide therapeutics for AD.
Funding Period: 2006-08-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Design, synthesis, and evaluation of bioactive small molecules
    Duy H Hua
    Department of Chemistry, 213 CBC Building, Kansas State University, Manhattan, KS 66506 040, USA
    Chem Rec 13:60-9. 2013
  2. pmc Inhibition of Acyl-CoA: cholesterol acyltransferase (ACAT), overexpression of cholesterol transporter gene, and protection of amyloid β (Aβ) oligomers-induced neuronal cell death by tricyclic pyrone molecules
    Laxman Pokhrel
    Department of Chemistry, 213 CBC Building, Kansas State University, Manhattan, Kansas 66503, USA
    J Med Chem 55:8969-73. 2012
  3. pmc Candidate anti-A beta fluorene compounds selected from analogs of amyloid imaging agents
    Hyun Seok Hong
    M I N D Institute and Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, 2805 50th Street, Sacramento, CA 95817, USA
    Neurobiol Aging 31:1690-9. 2010
  4. pmc Single-cell mechanics provides a sensitive and quantitative means for probing amyloid-beta peptide and neuronal cell interactions
    Valentin Lulevich
    Department of Chemistry, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 107:13872-7. 2010
  5. pmc Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity
    Izumi Maezawa
    Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, California 95618, USA
    J Biol Chem 286:3693-706. 2011
  6. ncbi Second-generation substituted quinolines as anticancer drugs for breast cancer
    Brian Heiniger
    Departments of Diagnostic Medicine Pathobiology, Kansas State University, Manhattan, KS 66506, USA
    Anticancer Res 30:3927-32. 2010
  7. pmc Anti-breast cancer agents, quinolines, targeting gap junction
    Julie Bernzweig
    Department of Diagnostic Medicine Pathobiology, Kansas State University, Manhattan, KS 66506, USA
    Med Chem 7:448-53. 2011
  8. ncbi Bioactivity and molecular targets of novel substituted quinolines in murine and human tumor cell lines in vitro
    Elisabeth M Perchellet
    Anti Cancer Drug Laboratory, Division of Biology, Ackert Hall, Kansas State University, Manhattan, KS 66506 4901, USA
    Int J Oncol 36:673-88. 2010
  9. ncbi Combinational treatment of gap junctional activator and tamoxifen in breast cancer cells
    Gunjan Gakhar
    Departments of Diagnostic Medicine Pathobiology, Kansas State University, Manhattan, USA
    Anticancer Drugs 21:77-88. 2010
  10. pmc Tricyclic pyrone compounds prevent aggregation and reverse cellular phenotypes caused by expression of mutant huntingtin protein in striatal neurons
    Eugenia Trushina
    Department of Chemistry, CBC Building, Kansas State University, Manhattan, KS 66506, USA
    BMC Neurosci 10:73. 2009

Scientific Experts

  • Duy Hua
  • Eugenia Trushina
  • Hyun Seok Hong
  • Aibin Shi
  • Elisabeth M Perchellet
  • Lee Way Jin
  • Sandeep Rana
  • Izumi Maezawa
  • Gunjan Gakhar
  • Jean Pierre H Perchellet
  • Srinivas K Battina
  • Brian Heiniger
  • Thu A Nguyen
  • Laxman Pokhrel
  • Julie Bernzweig
  • Keshar Prasain
  • Thu Annelise Nguyen
  • Valentin Lulevich
  • Lydia Barrigan
  • Kit S Lam
  • R Holland Cheng
  • Satyabrata Das
  • Chanran Ganta
  • Dolores J Takemoto
  • Huiping Zhao
  • Yang Wang
  • Kaiyan Lou
  • Kyeong Ok Chang
  • Thi D T Nguyen
  • Pavel I Zimin
  • Heike Wulff
  • Jianyu Lu
  • John C Voss
  • Christopher C Zimmer
  • Gang yu Liu
  • Robert Vassar
  • Ruiwu Liu
  • Madhu Budamagunta
  • Kyle R Crow
  • Feimeng Zhou
  • Deryl L Troyer
  • Chanran K Ganta
  • Yi Zhang
  • Snehalata Jena
  • Dingbo Lin
  • Rachel Allbaugh
  • Masaaki Tamura
  • Marla Pyle
  • Peter K Chiang
  • Deryl Troyer
  • Srinivas Battina
  • Ruben Diaz-Avalos
  • Bailing Xu
  • Nianhuan Yao

Detail Information

Publications20

  1. ncbi Design, synthesis, and evaluation of bioactive small molecules
    Duy H Hua
    Department of Chemistry, 213 CBC Building, Kansas State University, Manhattan, KS 66506 040, USA
    Chem Rec 13:60-9. 2013
    ..The discussion of these aforementioned projects may shed light on the future development of drug candidates in the fields of AD, cancer, and viral infections...
  2. pmc Inhibition of Acyl-CoA: cholesterol acyltransferase (ACAT), overexpression of cholesterol transporter gene, and protection of amyloid β (Aβ) oligomers-induced neuronal cell death by tricyclic pyrone molecules
    Laxman Pokhrel
    Department of Chemistry, 213 CBC Building, Kansas State University, Manhattan, Kansas 66503, USA
    J Med Chem 55:8969-73. 2012
    ..Five active compounds exhibited potencies in the nanomolar ranges. The multiple effects of the compounds on Aβ and cellular cholesterol pathways could be potential mechanisms underlying the protective effects in vivo...
  3. pmc Candidate anti-A beta fluorene compounds selected from analogs of amyloid imaging agents
    Hyun Seok Hong
    M I N D Institute and Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, 2805 50th Street, Sacramento, CA 95817, USA
    Neurobiol Aging 31:1690-9. 2010
    ..These fluorenes and future derivatives, therefore, have a potential use in AD therapy and research...
  4. pmc Single-cell mechanics provides a sensitive and quantitative means for probing amyloid-beta peptide and neuronal cell interactions
    Valentin Lulevich
    Department of Chemistry, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 107:13872-7. 2010
    ....
  5. pmc Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity
    Izumi Maezawa
    Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, California 95618, USA
    J Biol Chem 286:3693-706. 2011
    ..Our results suggest that AβO, generally considered a neurotoxin, may more potently cause neuronal damage indirectly by activating microglia in AD...
  6. ncbi Second-generation substituted quinolines as anticancer drugs for breast cancer
    Brian Heiniger
    Departments of Diagnostic Medicine Pathobiology, Kansas State University, Manhattan, KS 66506, USA
    Anticancer Res 30:3927-32. 2010
    ..PQ7-treated nu/nu mice showed a 100% regression of xenograft tumor growth of T47D cells. The results show that PQ7 has a promising role in exerting anti-tumor activity in human breast cancer cells...
  7. pmc Anti-breast cancer agents, quinolines, targeting gap junction
    Julie Bernzweig
    Department of Diagnostic Medicine Pathobiology, Kansas State University, Manhattan, KS 66506, USA
    Med Chem 7:448-53. 2011
    ..Our findings demonstrate that PQ15 has a promising role in exerting anti-cancer activity in human breast cancer cells...
  8. ncbi Bioactivity and molecular targets of novel substituted quinolines in murine and human tumor cell lines in vitro
    Elisabeth M Perchellet
    Anti Cancer Drug Laboratory, Division of Biology, Ackert Hall, Kansas State University, Manhattan, KS 66506 4901, USA
    Int J Oncol 36:673-88. 2010
    ....
  9. ncbi Combinational treatment of gap junctional activator and tamoxifen in breast cancer cells
    Gunjan Gakhar
    Departments of Diagnostic Medicine Pathobiology, Kansas State University, Manhattan, USA
    Anticancer Drugs 21:77-88. 2010
    ..Thus, a gap junctional activator, PQ1, could potentially alter either the length or dose of tamoxifen clinically used for breast cancer patients...
  10. pmc Tricyclic pyrone compounds prevent aggregation and reverse cellular phenotypes caused by expression of mutant huntingtin protein in striatal neurons
    Eugenia Trushina
    Department of Chemistry, CBC Building, Kansas State University, Manhattan, KS 66506, USA
    BMC Neurosci 10:73. 2009
    ..In the present study, we aimed to determine whether TP compounds could prevent aggregation and restore early cellular defects in primary embryonic striatal neurons from animal model representing HD...
  11. ncbi Synthesis, molecular targets, and antitumor activities of substituted tetrahydro-1-oxopyrano[4,3-b][1]benzopyrans and nanogels for drug delivery
    Elisabeth M Perchellet
    Anti Cancer Drug Laboratory, Division of Biology, Kansas State University, Manhattan, KS 66506 4901, USA
    Anticancer Agents Med Chem 9:864-76. 2009
    ..Since AQ10 is insoluble in water, PEG-PEI encapsulation represents a way to solubilize and deliver this as well as other poorly soluble compounds...
  12. pmc Inhibition of Alzheimer's amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo
    Hyun Seok Hong
    M I N D Institute and Department of Pathology, UC Davis Health System, Sacramento, California 95817, USA
    J Neurochem 108:1097-1108. 2009
    ..Our results suggest that CP2 might be beneficial to AD patients by preventing Abeta aggregation and disaggregating existing Abeta oligomers and protofibrils...
  13. ncbi Syntheses of tricyclic pyrones and pyridinones and protection of Abeta-peptide induced MC65 neuronal cell death
    Sandeep Rana
    Department of Chemistry, Kansas State University, Manhattan, KS 66506 3701, USA
    Bioorg Med Chem Lett 19:670-4. 2009
    ..49 and 1.25 microM, respectively, despite the lack of adenine moiety. Further investigation of tricyclic N2- and N5-analogs is warranted...
  14. pmc Protection of retinal cells from ischemia by a novel gap junction inhibitor
    Satyabrata Das
    Department of Biochemistry, Kansas State University, 141 Chalmers Hall, Manhattan, KS 66506, USA
    Biochem Biophys Res Commun 373:504-8. 2008
    ..This resulted in activation of caspase-3 which was prevented by PQ1, the gap junction inhibitor. Results demonstrate that novel gap junction inhibitors may provide a means to prevent retinal damage during ischemia...
  15. pmc Combination of nanogel polyethylene glycol-polyethylenimine and 6(hydroxymethyl)-1,4-anthracenedione as an anticancer nanomedicine
    Chanran Ganta
    Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
    J Nanosci Nanotechnol 8:2334-40. 2008
    ..These results suggest that PEG-PEI, usually used to deliver nucleic acids into cells, can also be used to deliver an insoluble small molecule anticancer drug, AQ10...
  16. pmc Synthesis and anti-breast cancer activities of substituted quinolines
    Aibin Shi
    Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA
    Bioorg Med Chem Lett 18:3364-8. 2008
    ..IC(50) values of three other quinolines are in the nanomolar range, a desirable range for pharmacological testing...
  17. pmc Total syntheses of (+/-)-ovalicin, C4(S *)-isomer, and its C5-analogs and anti-trypanosomal activities
    Duy H Hua
    Department of Chemistry, Kansas State University, Manhattan, KS 66506 3701, USA
    Bioorg Med Chem 16:5232-46. 2008
    ..Compounds 46 and a precursor, (3S( *),4R( *),5R( *),6R( *))-5-methoxy-4-[(E)-(1',5'-dimethylhexa-1',4'-dienyl)]-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octan-4-ol (28), may be explored for the development of anti-parasitic drugs...
  18. ncbi Antitumor triptycene analogs directly interact with isolated mitochondria to rapidly trigger markers of permeability transition
    Elisabeth M Perchellet
    Anti Cancer Drug Laboratory, Division of Biology, Ackert Hall, Kansas State University, Manhattan, KS 66506 4901, USA
    Anticancer Res 27:3259-71. 2007
    ..Because mitochondrial permeability transition (MPT) requires more than depolarization, antitumor TTs were tested for their ability to directly trigger specific markers of MPT in isolated mitochondria...
  19. ncbi Novel substituted 1,4-anthracenediones with antitumor activity directly induce permeability transition in isolated mitochondria
    Elisabeth M Perchellet
    Anti Cancer Drug Laboratory, Division of Biology, Kansas State University, Manhattan, KS 66506 4901, USA
    Int J Oncol 31:1231-41. 2007
    ....
  20. pmc Combining the rapid MTT formazan exocytosis assay and the MC65 protection assay led to the discovery of carbazole analogs as small molecule inhibitors of Abeta oligomer-induced cytotoxicity
    Hyun Seok Hong
    M I N D Institute and Department of Pathology, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA
    Brain Res 1130:223-34. 2007
    ..Both assays are simple, suitable for rapid screening of a large number of medicinal libraries, and amenable for automation...