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J Näslund

Publications and source records attributed to J Näslund.

At least 19 recordsLinked to original sources
PubMed2001

Structure of the dimethyl sulfoxide solvated thallium(III) ion in solution and in the solid state.

The structure and vibrational spectra of the dimethyl sulfoxide solvated thallium(III) ion have been studied in a dimethyl sulfoxide solution and in the solid state. X-ray crystallography shows a trigonal unit cell, space group R(-)3 (No. 148), for the [Tl(dmso)(6)](ClO(4))(3) compound with Z = 3, a = b = 11.9764(13) [11.8995(9)] A, c = 20.802(2) [20.467(2)] A, and V = 2584.0(5) [2509.9(4)] A(3) at 295 [150] K. The crystal structure comprises a highly symmetric hexakis(dimethyl sulfoxide)thallium(III) ion, with thallium in a (-)3 symmetry site and a Tl-O bond distance of 2.224(3) A at 295 K. The octahedral TlO(6) kernel is compressed along the threefold axis with an O-Tl-O bond angle of 96.20(11) degrees. The Tl-O-S bond angle of 120.7(2) degrees corresponds to a Tl.S distance of 3.292(2) A. One perchlorate ion centered on the (-)3 axis was described by a statistically disordered model. A low-temperature EXAFS study (10 K) resulted in the Tl-O and Tl.S distances of 2.221(4) and 3.282(6) A, respectively, consistent with a Tl-O-S bond angle of 120(1) degrees. The low Debye-Waller factors confirm a regular coordination without the disorder of the dimethyl sulfoxide ligands, which would have resulted from the alternative choice of space group R3 for the crystal structure. Raman and infrared spectra have been recorded and assigned, with the bands at 435 and 447 cm(-)(1) corresponding to the vibrational frequency of the symmetric and asymmetric Tl-O stretching modes, respectively. EXAFS data of a 0.5 mol dm(-3)thallium(III) trifluoromethanesulfonate in a dimethyl sulfoxide solution were consistent with that of a hexasolvated ion with mean Tl-O and Tl.S distances of 2.22(1) and 3.33(2) A, respectively, which correspond to a mean Tl-O-S bond angle of 124(2) degrees. The anomalously large disorder parameter for the Tl-O distances is consistent with a weak pseudo-Jahn-Teller effect. The (205)Tl, (13)C, and (1)H NMR spectra of the complex in solution show single signals at 1886, 39.5, and 2.3 ppm, respectively.

Cations↗
PubMed2001

The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation.

Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta-protein (Abeta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Abeta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Abeta42 and Abeta40 levels in plasma. Additionally, low levels of Abeta42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Abeta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Abeta. The finding of increased protofibril formation and decreased Abeta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Abeta protofibril formation leading to accelerated buildup of insoluble Abeta intra- and/or extracellularly.

Alzheimer Disease↗
PubMed2000

Solvation of the bismuth(III) ion by water, dimethyl sulfoxide, N,N'-dimethylpropyleneurea, and N,N-dimethylthioformamide. An EXAFS, large-angle X-ray scattering, and crystallographic structural study.

The structure of the solvated bismuth(III) ion in aqueous, dimethyl sulfoxide, N,N'-dimethylpropyleneurea, and N,N-dimethylthioformamide solution has been studied by means of EXAFS and large-angle X-ray scattering (LAXS). The crystal structures of the solid compounds octakis(dimethyl sulfoxide)bismuth(III) perchlorate, [Bi(OS(CH3)2)8](ClO4)3, hexakis(N,N'-dimethylpropyleneurea)bismuth(III) perchlorate, [Bi(OCN2(CH2)3(CH3)2)6](ClO4)3, and nonaaquabismuth(III) trifluoromethanesulfonate, [Bi(H2O)9](CF3SO3)3 (redetermination), have been determined. The aqueous solutions must be strongly acidic, since the hydrated bismuth(III) ion starts to hydrolyze into Bi6O4(OH)4(6+) complexes already at an excess of strong acid at 1.0 mol.dm-3. For very acidic aqueous perchlorate solutions, the LAXS and EXAFS data gave a satisfactory fit for eight-coordination of the bismuth(III) ion, with a mean Bi-O bond distance of 2.41(1) A. The crystal structure of octakis(dimethyl sulfoxide)bismuth(III) perchlorate shows that the bismuth(III) ion coordinates eight dimethyl sulfoxide molecules via the oxygen atoms in a distorted square antiprismatic configuration. The mean Bi-O bond distance is 2.43 A and the mean Bi...S distance 3.56 A. For the dimethyl sulfoxide solution, the corresponding mean distances were found to be 2.411(6) and 3.535(12) A. The N,N'-dimethylpropyleneurea-solvated bismuth(III) ion is octahedrally coordinated in both solid state and solution with the Bi-O bond distances of 2.324(5) and 2.322(3) A, respectively. The bismuth(III) ion is six-coordinated in the sulfur donor solvent N,N-dimethylthioformamide with a mean Bi-S bond distance of 2.794(8) A. A comparison with the structure of the solvated lanthanum(III) ion shows that the bismuth(III) ion is smaller for all coordination numbers. New effective ionic radii for the bismuth(III) ion in different coordination numbers are proposed, based on results in this study and in the literature.

Bismuth↗
PubMed2000

Steric effects control the structure of the solvated lanthanum(III) ion in aqueous, dimethyl sulfoxide, and N,N'-dimethylpropyleneurea solution. An EXAFS and large-angle X-ray scattering study.

The structure of the solvated lanthanum(III) ion has been determined in aqueous, dimethyl sulfoxide, and N,N'-dimethylpropyleneurea solution by means of the EXAFS and large-angle X-ray scattering (LAXS) techniques. The close agreement between the EXAFS spectra of solid nonaaqualanthanum(III) trifluoromethanesulfonate and of an aqueous lanthanum(III) perchlorate solution shows that the hydrated lanthanum(III) ion in aqueous solution most probably has the same structure as in the solid, i.e., nine water molecules coordinated in a tricapped trigonal prismatic configuration. The data analysis from EXAFS and LAXS measurements of the aqueous solution resulted in the La-O bond distances 2.52(2) and 2.65(3) A to the water molecules in the prism and the capping positions, respectively. The LAXS study shows a second hydration sphere consistent with approximately 18 water molecules at 4.63(2) A. The EXAFS spectra of solid octakis(dimethyl sulfoxide)lanthanum(III) trifluoromethanesulfonate and a dimethyl sulfoxide solution of this salt are also similar. The data analysis of EXAFS and LAXS measurements assuming eight-coordination around lanthanum yielded an La-O bond distance of 2.50(2) A, and an La...S distance of 3.70(3) A, giving an La-O-S angle of 133(2) degrees. The EXAFS data of an N,N'-dimethylpropyleneurea solution of lanthanum(III) trifluoromethanesulfonate gave the La-O bond distance 2.438(4) A and the La...C distance 3.41(2) A, which correspond to an La-O-C angle of 131(2) degrees. The La-O bond distance is consistent with seven-coordination around lanthanum, on the basis of the variation of the ionic radii of the lanthanum(III) ion with different coordination numbers.

Dimethyl Sulfoxide↗
PubMed2000

Controlling polymerization of beta-amyloid and prion-derived peptides with synthetic small molecule ligands.

The Alzheimer beta-amyloid peptide (Abeta) and a fragment of the prion protein have the capacity of forming amyloid-like fibrils when incubated under physiological conditions in vitro. Here we show that a small amyloid ligand, RO-47-1816/001, enhances this process severalfold by binding to amyloid molecules and apparently promote formation of the peptide-to-peptide bonds that join the monomers of the amyloid fibrils. This effect could be antagonized by other ligands, including analogues of RO-47-1816/001, as well as the structurally unrelated ligand Congo red. Analogues of RO-47-1816/001 with low affinity for amyloid did not display any antagonistic effect. In conclusion, these data suggest that synthetic molecules, and possibly also small natural substances present in the brain, may act in a chaperone-like fashion, promoting Abeta polymerization and growth of amyloid fibrils in vitro and possibly also in vivo. Furthermore, we demonstrate that small organic molecules can be used to inhibit the action of amyloid-enhancing compounds.

Amyloid beta-Peptides↗
PubMed2000

Quantification of Alzheimer amyloid beta peptides ending at residues 40 and 42 by novel ELISA systems.

BACKGROUND: The amyloid beta (Abeta) peptide is a key molecule in the pathogenesis of Alzheimer's disease. Reliable methods to detect and quantify soluble forms of this peptide in human biological fluids and in model systems, such as cell cultures and transgenic animals, are of great importance for further understanding the disease mechanisms. In this study, the application of new and highly specific ELISA systems for quantification of Abeta40 and Abeta42 (Abeta peptides ending at residues 40 or 42, respectively) in human cerebrospinal fluid (CSF) are presented. MATERIALS AND METHODS: Monoclonal antibodies WO-2, G2-10 and G2-11 were thoroughly characterized by (SPOT) epitope mapping and immunoprecipitation/mass spectrometry. We determined whether aggregation affected the binding capacities of the antibodies to synthetic peptides and whether components of the CSF affected the ability of the antibodies to bind synthetic Abeta1-40 and Abeta1-42 peptides. The stability of Abeta40 and Abeta42 in CSF during different temperature conditions was also studied to optimize sample handling from lumbar puncture to Abeta assay. RESULTS: The detection range for the ELISAs were 20-250 pM. The intra-assay variations were 2% and 3%, and the inter-assay variations were 2% and 10% for Abeta40 and Abeta42, respectively. The antibodies specifically detected the expected peptides with equal affinity for soluble and fibrillar forms of the peptide. The presence of CSF obstructed the recognition of synthetic peptides by the antibodies and the immunoreactivity of endogenous CSF Abeta decreased with increasing storage time and temperature. CONCLUSIONS: This study describes highly sensitive ELISAs with thoroughly characterized antibodies for quantification of Abeta40 and Abeta42, an important tool for the understanding of the pathogenesis of Alzheimer's disease. Our results pinpoint some of the difficulties associated with Abeta quantification and emphasize the importance of using a well-documented assay.

Albumins↗
PubMed1999

Amyloid fibril formation by pulmonary surfactant protein C.

Lung surfactant protein C (SP-C) is a lipopeptide that contains two fatty acyl (palmitoyl) chains bound via intrinsically labile thioester bonds. SP-C can transform from a monomeric alpha-helix into beta-sheet aggregates, reminiscent of structural changes that are supposed to occur in amyloid fibril formation. SP-C is here shown to form amyloid upon incubation in solution. Furthermore, one patient with pulmonary alveolar proteinosis (PAP, a rare disease where lung surfactant proteins and lipids accumulate in the airspaces) and six healthy controls have been studied regarding presence and composition of amyloid fibrils in the cell-free fraction of bronchoalveolar lavage (BAL) fluid. Abundant amyloid fibrils were found in BAL fluid from the patient with PAP and, in low amounts, in three of the six healthy controls. SDS-insoluble fibrillar material associated with PAP mainly consists of SP-C, in contrast to the fibrils found in controls. Fibrillated SP-C has to a significant extent lost the palmitoyl groups, and removal of the palmitoyl groups in vitro increases the rate of fibril formation.

Adolescent↗
PubMed1999

Medin: an integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common human amyloid.

Aortic medial amyloid is a form of localized amyloid that occurs in virtually all individuals older than 60 years. The importance and impact of the amyloid deposits are unknown. In this study we have purified a 5.5-kDa aortic medial amyloid component, by size-exclusion chromatography and RP-HPLC, from three individuals, and we have shown by amino acid sequence analysis that the amyloid is derived from an integral proteolytic fragment of lactadherin. Lactadherin is a 364-aa glycoprotein, previously known to be expressed by mammary epithelial cells as a cell surface protein and secreted as part of the milk fat globule membrane. The multidomain protein has a C-terminal domain showing homology to blood coagulation factors V and VIII. We found that the main constituent of aortic medial amyloid is a 50-aa-long peptide, here called medin, that is positioned within the coagulation factor-like domain of lactadherin. Our result is supported by the specific labeling of aortic medial amyloid in light and electron microscopy with two rabbit antisera raised against two synthetic peptides corresponding to different parts of medin. By using in situ hybridization we have shown that lactadherin is expressed by aortic medial smooth muscle cells. Furthermore, one of the synthetic peptides forms amyloid-like fibrils in vitro. Lactadherin was not previously known to be an amyloid precursor protein or to be expressed in aortic tissue. The structure of lactadherin may implicate an important regulatory function in the aorta.

Aged↗
PubMed1999

Endogenous proteins controlling amyloid beta-peptide polymerization. Possible implications for beta-amyloid formation in the central nervous system and in peripheral tissues.

We report that certain plasma proteins, at physiological concentrations, are potent inhibitors of amyloid beta-peptide (Abeta) polymerization. These proteins are also present in cerebrospinal fluid, but at low concentrations having little or no effect on Abeta. Thirteen proteins representing more than 90% of the protein content in plasma and cerebrospinal fluid were studied. Quantitatively, albumin was the most important protein, representing 60% of the total amyloid inhibitory activity, followed by alpha1-antitrypsin and immunoglobulins A and G. Albumin suppressed amyloid formation by binding to the oligomeric or polymeric Abeta, blocking a further addition of peptide. This effect was also observed when the incorporation of labeled Abeta into genuine beta-amyloid in tissue section was studied. The Abeta and the anti-diabetic drug tolbutamide apparently bind to the same site on albumin. Tolbutamide displaces Abeta from albumin, increasing its free concentration and enhancing amyloid formation. The present results suggest that several endogenous proteins are negative regulators of amyloid formation. Plasma contains at least 300 times more amyloid inhibitory activity than cerebrospinal fluid. These findings may provide one explanation as to why beta-amyloid deposits are not found in peripheral tissues but are only found in the central nervous system. Moreover, the data suggest that some drugs that display an affinity for albumin may enhance beta-amyloid formation and promote the development of Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed1997

Controlling amyloid beta-peptide fibril formation with protease-stable ligands.

We have previously shown that short peptides incorporating the sequence KLVFF can bind to the approximately 40amino acid residue Alzheimer amyloid beta-peptide (Abeta) and disrupt amyloid fibril formation (Tjernberg, L. O., Näslund, J., Lindqvist, F., Johansson, J., Karlström, A. R., Thyberg, J., Terenius, L., and Nordstedt, C. (1996) J. Biol. Chem. 271, 8545-8548). Here, it is shown that KLVFF binds stereospecifically to the homologous sequence in Abeta (i.e. Abeta16-20). Molecular modeling suggests that association of the two homologous sequences leads to the formation of an atypical anti-parallel beta-sheet structure stabilized primarily by interaction between the Lys, Leu, and COOH-terminal Phe. By screening combinatorial pentapeptide libraries exclusively composed of D-amino acids, several ligands with a general motif containing phenylalanine in the second position and leucine in the third position were identified. Ligands composed of D-amino acids were not only capable of binding Abeta but also prevented formation of amyloid-like fibrils. These ligands are protease-resistant and may thus be useful as experimental agents against amyloid fibril formation in vivo.

Amino Acids↗
PubMed1997

Generation of Alzheimer amyloid beta peptide through nonspecific proteolysis.

Polymerization of Alzheimer amyloid beta peptide (Abeta) into amyloid fibrils is associated with resistance to proteolysis and tissue deposition. Here, it was investigated whether Abeta might be generated as a protease-resistant core from a polymerized precursor. A 100-amino acid C-terminal fragment of the Alzheimer beta-amyloid precursor protein (C100), containing the Abeta and cytoplasmic domains, polymerized both when inserted into membranes and after purification. When subjected to digestion using the nonspecific enzyme proteinase K, the cytoplasmic domain of C100 was degraded, whereas the Abeta domain remained intact. In contrast, dissociated C100 polymers were almost completely degraded by proteinase K. Mammalian cells transfected with the human Alzheimer beta-amyloid precursor gene contained a fragment corresponding to C100, which needed similar harsh conditions to be dissolved, as did polymers formed by purified C100. Hence, it was concluded that C100 polymers are formed in mammalian cells. These results suggest that the C terminus of Abeta can be generated by nonspecific proteases, acting on a polymerized substrate, rather than a specific gamma-secretase. This offers an explanation of how the Abeta peptide can be formed in organelles containing proteases capable of cleaving most peptide bonds.

Alzheimer Disease↗
PubMed1996

Arrest of beta-amyloid fibril formation by a pentapeptide ligand.

Polymerization of amyloid beta-peptide (Abeta) into amyloid fibrils is a critical step in the pathogenesis of Alzheimer's disease. Here, we show that peptides incorporating a short Abeta fragment (KLVFF; Abeta16-20) can bind full-length Abeta and prevent its assembly into amyloid fibrils. Through alanine substitution, it was demonstrated that amino acids Lys16, Leu17, and Phe20 are critical for binding to Abeta and inhibition of Abeta fibril formation. A mutant Abeta molecule, in which these residues had been substituted, had a markedly reduced capability of forming amyloid fibrils. The present data suggest that residues Abeta16-20 serve as a binding sequence duringA beta polymerization and fibril formation. Moreover, the present KLVFF peptide may serve as a lead compound for the development of peptide and non-peptide agents aimed at inhibiting Abeta amyloidogenesis in vivo.

Amino Acid Sequence↗
PubMed1996

High-resolution separation of amyloid beta-peptides: structural variants present in Alzheimer's disease amyloid.

In Alzheimer's disease (AD), one of the cardinal neuropathological signs is deposition of amyloid, primarily consisting of the amyloid beta-peptide (Abeta). Structural variants of AD-associated Abeta peptides have been difficult to purify by high-resolution chromatographic techniques. We therefore developed a novel chromatographic protocol, enabling high-resolution reverse-phase liquid chromatography (RPLC) purification of Abeta variants displaying very small structural differences. By using a combination of size-exclusion chromatography and the novel RPLC protocol, Abeta peptides extracted from AD amyloid were purified and subsequently characterized. Structural analysis by microsequencing and electrospray-ionization mass spectrometry revealed that the RPLC system resolved a complex mixture of Abeta variants terminating at either residue 40 or 42. Abeta variants differing by as little as one amino acid residue could be purified rapidly to apparent homogeneity. The resolution of the system was further illustrated by its ability to separate the structural isomers of Abeta1-40. The present chromatography system might provide further insight into the role of N-terminally and posttranslationally modified Abeta variants, because each variant can now be studied individually.

Alzheimer Disease↗
PubMed1996

Beta-amyloid protein protein precursor expression in lacrimal glands and tear fluid.

PURPOSE: Proteases in tear fluid play important roles in the regulation of corneal wound healing. Inhibitors of proteolytic activity are major modulators of the associated events. Although it is known that various enzyme inhibitors exist in tear fluid, it is not known whether certain isoforms of the beta-amyloid protein precursor (beta-APP), a potent inhibitor of serine proteases, are present in tear fluid. The purpose of this study was to investigate whether beta-APP can be detected in human tear fluid and, if so, to determine the isoform composition and cellular origin. METHODS: Tear fluid was collected from healthy volunteers. The beta-APP was identified and characterized by immunoblotting using antibodies specific for domains of the beta-APP. The protein was characterized further by ion exchange chromatography. Expression of the beta-APP gene was studied using in situ hybridization and RNA-RNA solution hybridization assay. RESULTS: beta-APP with protease inhibitory properties was identified in all samples of human tear fluid. Immunologic analysis revealed that it had been processed proteolytically before secretion. Gene expression studies showed that the beta-APP gene was expressed in lacrimal glands, particularly in acinar cells. The gene transcript almost exclusively corresponded to beta-APP containing the protease inhibitor insert. CONCLUSIONS: beta-APP is expressed in lacrimal glands and subsequently is secreted into tear fluid. Because the bulk of the beta-APP contained the protease inhibitor insert, the authors propose that beta-APP is an important regulator of proteolysis in tear fluid and that possibly it plays a role in the events associated with corneal wound healing. This suggests a novel physiological function of beta-APP in addition to those previously described-regulation of blood coagulation and cell growth.

Adult↗
PubMed1995

Characterization of stable complexes involving apolipoprotein E and the amyloid beta peptide in Alzheimer's disease brain.

Genetic evidence suggests a role for apolipoprotein E (apoE) in Alzheimer's disease (AD) amyloidogenesis. Here, amyloid-associated apoE from 32 AD patients was purified and characterized. We found that brain amyloid-associated apoE apparently exists not as free molecules but as complexes with polymers of the amyloid beta peptide (A beta). Brain A beta-apoE complexes were detected irrespective of the apoE genotype, and similar complexes could be mimicked in vitro. The fine structure of purified A beta-apoE complexes was fibrillar, and immunogold labeling revealed apoE immunoreactivity along the fibrils. Thus, we conclude that A beta-apoE complexes are principal components of AD-associated brain amyloid and that the data presented here support a role for apoE in the pathogenesis of AD.

Aged↗