Design of small molecules that target metal-A{beta} species and regulate metal-induced A{beta} aggregation and neurotoxicity.

Abstract:

:The accumulation of metal ions and amyloid-β (Aβ) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-Aβ-associated pathways in AD, development of chemical tools to target metal-Aβ species is desired. Only a few efforts, however, have been reported. Here, we report bifunctional small molecules, N-(pyridin-2-ylmethyl)aniline (L2-a) and N(1),N(1)-dimethyl-N(4)-(pyridin-2-ylmethyl)benzene-1,4-diamine (L2-b) that can interact with both metal ions and Aβ species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced Aβ aggregation and neurotoxicity were modulated in vitro as well as in human neuroblastoma cells. Furthermore, treatment of human AD brain tissue homogenates containing metal ions and Aβ species with L2-b showed disassembly of Aβ aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-Aβ-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.

authors

Choi JS,Braymer JJ,Nanga RP,Ramamoorthy A,Lim MH

doi

10.1073/pnas.1006091107

subject

Has Abstract

pub_date

2010-12-21 00:00:00

pages

21990-5

issue

51

eissn

0027-8424

issn

1091-6490

pii

1006091107

journal_volume

107

pub_type

杂志文章
  • The crystal structure and mutational analysis of a novel RNA-binding domain found in the human Tap nuclear mRNA export factor.

    abstract::The Tap protein mediates the sequence nonspecific nuclear export of cellular mRNAs as well as the sequence-specific export of retroviral mRNAs bearing the constitutive transport element (CTE). Previously, the structures of individual Tap subdomains, including ribonucleoprotein and leucine-rich repeat domains, have bee...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.042698599

    authors: Ho DN,Coburn GA,Kang Y,Cullen BR,Georgiadis MM

    更新日期:2002-02-19 00:00:00

  • Brain-specific deletion of neuropathy target esterase/swisscheese results in neurodegeneration.

    abstract::Neuropathy target esterase (NTE) is a neuronal membrane protein originally identified for its property to be modified by organo-phosphates (OPs), which in humans cause neuropathy characterized by axonal degeneration. Drosophila mutants for the homolog gene of NTE, swisscheese (sws), indicated a possible involvement of...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0401030101

    authors: Akassoglou K,Malester B,Xu J,Tessarollo L,Rosenbluth J,Chao MV

    更新日期:2004-04-06 00:00:00

  • The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation.

    abstract::Protein-protein and protein-ligand interactions are ubiquitous in a biological cell. Here, we report a comprehensive study of the distribution of protein-ligand interaction sites, namely ligand-binding pockets, around protein-protein interfaces where protein-protein interactions occur. We inspected a representative se...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1117768109

    authors: Gao M,Skolnick J

    更新日期:2012-03-06 00:00:00

  • Ocean acidification causes bleaching and productivity loss in coral reef builders.

    abstract::Ocean acidification represents a key threat to coral reefs by reducing the calcification rate of framework builders. In addition, acidification is likely to affect the relationship between corals and their symbiotic dinoflagellates and the productivity of this association. However, little is known about how acidificat...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0804478105

    authors: Anthony KR,Kline DI,Diaz-Pulido G,Dove S,Hoegh-Guldberg O

    更新日期:2008-11-11 00:00:00

  • Parallel RNA and DNA analysis after deep sequencing (PRDD-seq) reveals cell type-specific lineage patterns in human brain.

    abstract::Elucidating the lineage relationships among different cell types is key to understanding human brain development. Here we developed parallel RNA and DNA analysis after deep sequencing (PRDD-seq), which combines RNA analysis of neuronal cell types with analysis of nested spontaneous DNA somatic mutations as cell lineag...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2006163117

    authors: Huang AY,Li P,Rodin RE,Kim SN,Dou Y,Kenny CJ,Akula SK,Hodge RD,Bakken TE,Miller JA,Lein ES,Park PJ,Lee EA,Walsh CA

    更新日期:2020-06-23 00:00:00

  • Trafficking of gap junction channels at a vertebrate electrical synapse in vivo.

    abstract::Trafficking and turnover of transmitter receptors required to maintain and modify the strength of chemical synapses have been characterized extensively. In contrast, little is known regarding trafficking of gap junction components at electrical synapses. By combining ultrastructural and in vivo physiological analysis ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1121557109

    authors: Flores CE,Nannapaneni S,Davidson KG,Yasumura T,Bennett MV,Rash JE,Pereda AE

    更新日期:2012-02-28 00:00:00

  • Spiking activity in the human hippocampus prior to encoding predicts subsequent memory.

    abstract::Encoding activity in the medial temporal lobe, presumably evoked by the presentation of stimuli (postonset activity), is known to predict subsequent memory. However, several independent lines of research suggest that preonset activity also affects subsequent memory. We investigated the role of preonset and postonset s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2001338117

    authors: Urgolites ZJ,Wixted JT,Goldinger SD,Papesh MH,Treiman DM,Squire LR,Steinmetz PN

    更新日期:2020-06-16 00:00:00

  • beta-Glucuronidase from Escherichia coli as a gene-fusion marker.

    abstract::We have developed a gene-fusion system based on the Escherichia coli beta-glucuronidase gene (uidA). The uidA gene has been cloned from E. coli K-12 and its entire nucleotide sequence has been determined. beta-Glucuronidase has been purified to homogeneity and characterized. The enzyme has a subunit molecular weight o...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.22.8447

    authors: Jefferson RA,Burgess SM,Hirsh D

    更新日期:1986-11-01 00:00:00

  • Lifting cusp forms to Maass forms with an application to partitions.

    abstract::For 2 < k [abstract: see text] we define lifts of cuspidal Poincaré series in S(k)(Gamma(0)(N)) to weight 2 - k harmonic weak Maass forms. This construction answers a question of Dyson by providing the general framework "explaining" Ramanujan's mock theta functions. As an application, we show that the number of partit...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0611414104

    authors: Bringmann K,Ono K

    更新日期:2007-03-06 00:00:00

  • DNA probes that store mechanical information reveal transient piconewton forces applied by T cells.

    abstract::The advent of molecular tension probes for real-time mapping of piconewton forces in living systems has had a major impact on mechanobiology. For example, DNA-based tension probes have revealed roles for mechanics in platelet, B cell, T cell, and fibroblast function. Nonetheless, imaging short-lived forces transmitted...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1904034116

    authors: Ma R,Kellner AV,Ma VP,Su H,Deal BR,Brockman JM,Salaita K

    更新日期:2019-08-20 00:00:00

  • Histone octamer dissociation is not required for transcript elongation through arrays of nucleosome cores by phage T7 RNA polymerase in vitro.

    abstract::We have examined whether dissociation of the histone octamer is required for elongation of RNA transcripts through arrays of nucleosome cores in vitro. Control or dimethyl suberimidate-crosslinked histone octamers were reconstituted onto supercoiled, closed circular pT207-18 DNA, which contains tandemly repeated 207-b...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.13.6203

    authors: O'Neill TE,Smith JG,Bradbury EM

    更新日期:1993-07-01 00:00:00

  • A role for ultraviolet A in solar mutagenesis.

    abstract::It is well established that exposure to solar UVB (290-320 nm) gives rise to mutations in oncogenes and tumor suppressor genes that initiate the molecular cascade toward skin cancer. Although UVA (320-400 nm) has also been implicated in multistage photocarcinogenesis, its potential contribution to sunlight mutagenesis...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.6.2350

    authors: Drobetsky EA,Turcotte J,Châteauneuf A

    更新日期:1995-03-14 00:00:00

  • J protein cochaperone of the mitochondrial inner membrane required for protein import into the mitochondrial matrix.

    abstract::The major Hsp70 of the mitochondrial matrix (Ssc1 in yeast) is critically important for the translocation of proteins from the cytosol, across the mitochondrial inner membrane, and into the matrix. Tim44, a peripheral inner membrane protein with limited sequence similarity to the J domain of J-type cochaperones, tethe...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1936150100

    authors: D'Silva PD,Schilke B,Walter W,Andrew A,Craig EA

    更新日期:2003-11-25 00:00:00

  • Purification and identification of pituitary cytotropic factor.

    abstract::It has been shown that the pituitary contains a cytotropic factor (CTF) that stimulates the secretion of catecholamines by dopaminergic neurons of the hypothalamus. In the present study, CTF was purified from rat pituitaries and found by means of mass spectrometric analysis to be adenosine. This finding was corroborat...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.12.5351

    authors: Porter JC,Ijames CF,Wang TC,Markey SP

    更新日期:1995-06-06 00:00:00

  • Large extinctions in an evolutionary model: the role of innovation and keystone species.

    abstract::The causes of major and rapid transitions observed in biological macroevolution as well as in the evolution of social systems are a subject of much debate. Here we identify the proximate causes of crashes and recoveries that arise dynamically in a model system in which populations of (molecular) species coevolve with ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.032618499

    authors: Jain S,Krishna S

    更新日期:2002-02-19 00:00:00

  • Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1-40)] in bilayer membranes.

    abstract::We have recently shown that the Alzheimer disease 40-residue amyloid beta-protein [A beta P-(1-40)] can form cation-selective channels when incorporated into planar lipid bilayers by fusion of liposomes containing the peptide. Since A beta P-(1-40) comprises portions of the putative extracellular and membrane-spanning...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.22.10573

    authors: Arispe N,Pollard HB,Rojas E

    更新日期:1993-11-15 00:00:00

  • Effects of methylation on a synthetic polynucleotide: the B--Z transition in poly(dG-m5dC).poly(dG-m5dC).

    abstract::We have compared the behavior in solution of the synthetic polynucleotide poly(dG-m5dC).poly(dG-m5dC) with that of the unmethylated polynucleotide poly(dG-dC).poly(dG-dC). In solutions containing high concentrations of salt, poly(dG-dC).poly(dG-dC) is known to exhibit altered circular dichroic and absorption spectra c...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.3.1619

    authors: Behe M,Felsenfeld G

    更新日期:1981-03-01 00:00:00

  • The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions.

    abstract::Usher syndrome type 1 (USH1) patients suffer from sensorineuronal deafness, vestibular dysfunction, and visual impairment. Several genetic loci have been linked to USH1, and four of the relevant genes have been identified. They encode the unconventional myosin VIIa, the PDZ-domain protein harmonin, and the putative ad...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.232579599

    authors: Siemens J,Kazmierczak P,Reynolds A,Sticker M,Littlewood-Evans A,Müller U

    更新日期:2002-11-12 00:00:00

  • A G protein-coupled receptor with low density lipoprotein-binding motifs suggests a role for lipoproteins in G-linked signal transduction.

    abstract::We have isolated and analyzed a cDNA from the central nervous system of the mollusc Lymnaea stagnalis encoding a putative receptor, which might be a natural hybrid between two different classes of receptor proteins. Preceded by a signal peptide, two types of repeated sequences are present in the N-terminal part of the...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.91.11.4816

    authors: Tensen CP,Van Kesteren ER,Planta RJ,Cox KJ,Burke JF,van Heerikhuizen H,Vreugdenhil E

    更新日期:1994-05-24 00:00:00

  • Genetic exchange and plasmid transfers in Borrelia burgdorferi sensu stricto revealed by three-way genome comparisons and multilocus sequence typing.

    abstract::Comparative genomics of closely related bacterial isolates is a powerful method for uncovering virulence and other important genome elements. We determined draft sequences (8-fold coverage) of the genomes of strains JD1 and N40 of Borrelia burgdorferi sensu stricto, the causative agent of Lyme disease, and we compared...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0402745101

    authors: Qiu WG,Schutzer SE,Bruno JF,Attie O,Xu Y,Dunn JJ,Fraser CM,Casjens SR,Luft BJ

    更新日期:2004-09-28 00:00:00

  • Specificity of O-glycosylation in enhancing the stability and cellulose binding affinity of Family 1 carbohydrate-binding modules.

    abstract::The majority of biological turnover of lignocellulosic biomass in nature is conducted by fungi, which commonly use Family 1 carbohydrate-binding modules (CBMs) for targeting enzymes to cellulose. Family 1 CBMs are glycosylated, but the effects of glycosylation on CBM function remain unknown. Here, the effects of O-man...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1402518111

    authors: Chen L,Drake MR,Resch MG,Greene ER,Himmel ME,Chaffey PK,Beckham GT,Tan Z

    更新日期:2014-05-27 00:00:00

  • Ocean melting of the Zachariae Isstrøm and Nioghalvfjerdsfjorden glaciers, northeast Greenland.

    abstract::Zachariae Isstrøm (ZI) and Nioghalvfjerdsfjorden (79N) are marine-terminating glaciers in northeast Greenland that hold an ice volume equivalent to a 1.1-m global sea level rise. ZI lost its floating ice shelf, sped up, retreated at 650 m/y, and experienced a 5-gigaton/y mass loss. Glacier 79N has been more stable des...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2015483118

    authors: An L,Rignot E,Wood M,Willis JK,Mouginot J,Khan SA

    更新日期:2021-01-12 00:00:00

  • Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation.

    abstract::Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1615413114

    authors: Rothhammer V,Kenison JE,Tjon E,Takenaka MC,de Lima KA,Borucki DM,Chao CC,Wilz A,Blain M,Healy L,Antel J,Quintana FJ

    更新日期:2017-02-21 00:00:00

  • Remodeling in bone without osteocytes: billfish challenge bone structure-function paradigms.

    abstract::A remarkable property of tetrapod bone is its ability to detect and remodel areas where damage has accumulated through prolonged use. This process, believed vital to the long-term health of bone, is considered to be initiated and orchestrated by osteocytes, cells within the bone matrix. It is therefore surprising that...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1412372111

    authors: Atkins A,Dean MN,Habegger ML,Motta PJ,Ofer L,Repp F,Shipov A,Weiner S,Currey JD,Shahar R

    更新日期:2014-11-11 00:00:00

  • Metformin increases degradation of phospholamban via autophagy in cardiomyocytes.

    abstract::Phospholamban (PLN) is an effective inhibitor of the sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA). Here, we examined PLN stability and degradation in primary cultured mouse neonatal cardiomyocytes (CMNCs) and mouse hearts using immunoblotting, molecular imaging, and [(35)S]methionine pulse-chase experiments, tog...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1508815112

    authors: Teng AC,Miyake T,Yokoe S,Zhang L,Rezende LM Jr,Sharma P,MacLennan DH,Liu PP,Gramolini AO

    更新日期:2015-06-09 00:00:00

  • Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells.

    abstract::Retinoic acid receptor beta (RAR beta), which codes for a nuclear receptor for retinoic acid, is localized in a chromosomal region frequently deleted in lung cancer cells. The gene is expressed in normal lung tissue and in the majority of the cell lines derived from lung tumors but not in most of the lines derived fro...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.3.985

    authors: Houle B,Rochette-Egly C,Bradley WE

    更新日期:1993-02-01 00:00:00

  • Transformation of breast cells by truncated neurokinin-1 receptor is secondary to activation by preprotachykinin-A peptides.

    abstract::Breast cancer remains the cancer with the highest mortality among women in the United States. Peptides derived from the oncogenic Tac1 gene (full transcript: betaPPT-A) stimulate the proliferation of breast cancer cells (BCCs) via seven-transmembrane G protein-coupled neurokinin 1 (NK1) and NK2 receptors. The NK1 gene...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0506351102

    authors: Patel HJ,Ramkissoon SH,Patel PS,Rameshwar P

    更新日期:2005-11-29 00:00:00

  • Hyperpolarized water as an authentic magnetic resonance imaging contrast agent.

    abstract::Pure water in a highly (1)H spin-polarized state is proposed as a contrast-agent-free contrast agent to visualize its macroscopic evolution in aqueous media by MRI. Remotely enhanced liquids for image contrast (RELIC) utilizes a (1)H signal of water that is enhanced outside the sample in continuous-flow mode and immed...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0610540104

    authors: McCarney ER,Armstrong BD,Lingwood MD,Han S

    更新日期:2007-02-06 00:00:00

  • Insulin receptors in human circulating cells and fibroblasts.

    abstract::Human lymphocytes obtained from fasted adult subjects and cultured human tumor lymphocytes were investigated for specific insulin receptors. By use of monoiodoinsulin, specific insulin binding sites were demonstrated in peripheral human lymphocytes, cultured human lymphocytes, and in other types of human circulating c...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.69.3.747

    authors: Gavin JR 3rd,Roth J,Jen P,Freychet P

    更新日期:1972-03-01 00:00:00

  • The rise and fall of a networked society: a formal model.

    abstract::In a well networked community, there is intense social interaction, and information disseminates briskly and broadly. This is important if the environment is volatile (i.e., keeps changing) and individuals never stop searching for fresh opportunities. Here, we present a simple model that attributes the rise of a dynam...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0305684101

    authors: Marsili M,Vega-Redondo F,Slanina F

    更新日期:2004-02-10 00:00:00