The Experts below are selected from a list of 16272 Experts worldwide ranked by ideXlab platform
Christer Nordstedt - One of the best experts on this subject based on the ideXlab platform.
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A molecular model of Alzheimer amyloid beta-peptide Fibril Formation.
The Journal of biological chemistry, 2020Co-Authors: Lars O. Tjernberg, David J. E. Callaway, Agneta Tjernberg, Solveig Hahne, Christina Lilliehöök, Lars Terenius, Johan Thyberg, Christer NordstedtAbstract:Abstract Polymerization of the amyloid beta (Aβ) peptide into protease-resistant Fibrils is a significant step in the pathogenesis of Alzheimer’s disease. It has not been possible to obtain detailed structural inFormation about this process with conventional techniques because the peptide has limited solubility and does not form crystals. In this work, we present experimental results leading to a molecular level model for Fibril Formation. Systematically selected Aβ-fragments containing the Aβ16–20sequence, previously shown essential for Aβ-Aβ binding, were incubated in a physiological buffer. Electron microscopy revealed that the shortest Fibril-forming sequence was Aβ14–23. Substitutions in this decapeptide impaired Fibril Formation and deletion of the decapeptide from Aβ1–42 inhibited Fibril Formation completely. All studied peptides that formed Fibrils also formed stable dimers and/or tetramers. Molecular modeling of Aβ14–23 oligomers in an antiparallel β-sheet conFormation displayed favorable hydrophobic interactions stabilized by salt bridges between all charged residues. We propose that this decapeptide sequence forms the core of Aβ-Fibrils, with the hydrophobic C terminus folding over this core. The identification of this fundamental sequence and the implied molecular model could facilitate the design of potential inhibitors of amyloidogenesis.
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a molecular model of alzheimer amyloid β peptide Fibril Formation
Journal of Biological Chemistry, 1999Co-Authors: Lars O. Tjernberg, David J. E. Callaway, Agneta Tjernberg, Solveig Hahne, Christina Lilliehöök, Lars Terenius, Johan Thyberg, Christer NordstedtAbstract:Abstract Polymerization of the amyloid beta (Aβ) peptide into protease-resistant Fibrils is a significant step in the pathogenesis of Alzheimer’s disease. It has not been possible to obtain detailed structural inFormation about this process with conventional techniques because the peptide has limited solubility and does not form crystals. In this work, we present experimental results leading to a molecular level model for Fibril Formation. Systematically selected Aβ-fragments containing the Aβ16–20sequence, previously shown essential for Aβ-Aβ binding, were incubated in a physiological buffer. Electron microscopy revealed that the shortest Fibril-forming sequence was Aβ14–23. Substitutions in this decapeptide impaired Fibril Formation and deletion of the decapeptide from Aβ1–42 inhibited Fibril Formation completely. All studied peptides that formed Fibrils also formed stable dimers and/or tetramers. Molecular modeling of Aβ14–23 oligomers in an antiparallel β-sheet conFormation displayed favorable hydrophobic interactions stabilized by salt bridges between all charged residues. We propose that this decapeptide sequence forms the core of Aβ-Fibrils, with the hydrophobic C terminus folding over this core. The identification of this fundamental sequence and the implied molecular model could facilitate the design of potential inhibitors of amyloidogenesis.
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arrest of amyloid Fibril Formation by a pentapeptide ligand
Journal of Biological Chemistry, 1996Co-Authors: Lars O. Tjernberg, Lars Terenius, Johan Thyberg, Jan Naslund, Fredrik Lindqvist, Jan Johansson, Anders R Karlstrom, Christer NordstedtAbstract:Abstract Polymerization of amyloid β-peptide (Aβ) into amyloid Fibrils is a critical step in the pathogenesis of Alzheimer's disease. Here, we show that peptides incorporating a short Aβ fragment (KLVFF; Aβ) can bind full-length Aβ and prevent its assembly into amyloid Fibrils. Through alanine substitution, it was demonstrated that amino acids Lys, Leu, and Phe are critical for binding to Aβ and inhibition of Aβ Fibril Formation. A mutant Aβ molecule, in which these residues had been substituted, had a markedly reduced capability of forming amyloid Fibrils. The present data suggest that residues Aβ serve as a binding sequence during Aβ 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 Aβ amyloidogenesis in vivo.
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arrest of beta amyloid Fibril Formation by a pentapeptide ligand
Journal of Biological Chemistry, 1996Co-Authors: Lars O. Tjernberg, Lars Terenius, Johan Thyberg, Jan Naslund, Fredrik Lindqvist, Jan Johansson, Anders R Karlstrom, Christer NordstedtAbstract: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.
Nobutada Tashiro - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Aβ Fibril Formation and Aβ-induced cytotoxicity by senile plaque-associated proteins
Neuroscience Letters, 2000Co-Authors: Akira Monji, Ichiro Yoshida, Ken-ichiro Tashiro, Yoshihito Hayashi, Kazunori Matsuda, Nobutada TashiroAbstract:Aβ neurotoxicity is generally believed to require Aβ Fibril Formation. The prevention of Aβ Fibril Formation thus seems to be a promising strategy for the treatment of AD. Recent studies have shown senile plaque-associated proteins such as laminin to have an inhibitory effect on both Aβ40 and Aβ42 Fibril Formation in vitro. In the present study, we thus investigated whether or not midkine (MK) and α2-macroglobulin (α2M), both of which are also senile plaque-associated proteins like laminin, affect Aβ Fibril Formation and Aβ-induced cytotoxicity. The present study demonstrated that both MK and α2M inhibit both Aβ Fibril Formation and Aβ-induced cytotoxicity in PC12 cells. The confirmation of the present results based on in vivo experiments is called for in future studies to clarify whether or not senile plaque-associated proteins such as MK and α2M can be a model for therapeutic agents in the treatment of AD.
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Inhibition of A beta Fibril Formation and A beta-induced cytotoxicity by senile plaque-associated proteins.
Neuroscience letters, 2000Co-Authors: Akira Monji, Ichiro Yoshida, Yoshihito Hayashi, Kazunori Matsuda, K Tashiro, Nobutada TashiroAbstract:A beta neurotoxicity is generally believed to require A beta Fibril Formation. The prevention of A beta Fibril Formation thus seems to be a promising strategy for the treatment of AD. Recent studies have shown senile plaque-associated proteins such as laminin to have an inhibitory effect on both A beta40 and A beta42 Fibril Formation in vitro. In the present study, we thus investigated whether or not midkine (MK) and alpha2-macroglobulin (alpha2M), both of which are also senile plaque-associated proteins like laminin, affect A beta Fibril Formation and A beta-induced cytotoxicity. The present study demonstrated that both MK and alpha2M inhibit both A beta Fibril Formation and A beta-induced cytotoxicity in PC12 cells. The confirmation of the present results based on in vivo experiments is called for in future studies to clarify whether or not senile plaque-associated proteins such as MK and alpha2M can be a model for therapeutic agents in the treatment of AD.
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Laminin inhibits Aβ40 Fibril Formation promoted by apolipoprotein E4 in vitro
Brain Research, 1998Co-Authors: Akira Monji, Ichiro Yoshida, Ken-ichiro Tashiro, Yoshihito Hayashi, Nobutada TashiroAbstract:Abstract The aggregation of soluble Aβ into insoluble amyloid Fibrils is believed to be an important step in the pathogenesis of Alzheimer's disease (AD) and the prevention of this process therefore seems to be a promising strategy for the treatment of AD. Both apolipoprotein E(apoE) and laminin are known to play important roles in the regeneration of the central nervous system and both are known to accumulate in the senile plaques of the AD brains. In the present study, we therefore investigated whether or not laminin has any effect on Aβ40 Fibril Formation promoted by apoE4 in vitro. A thioflavine-T fluorometric assay and electron microscopic observations using negative staining together demonstrated that laminin inhibits Aβ40 Fibril Formation in vitro while it also inhibits Aβ40 Fibril Formation promoted by apoE4. These results suggested that either laminin or its derivatives may thus be effective as therapeutic agents for AD.
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Laminin inhibits Aβ42 Fibril Formation in vitro
Brain Research, 1998Co-Authors: Akira Monji, Ichiro Yoshida, Ken-ichiro Tashiro, Yoshihito Hayashi, Nobutada TashiroAbstract:Abstract In the present study, we investigated whether or not laminin inhibits A β 42 Fibril Formation in the same manner as A β 40. Both a thioflavine-T fluorometric assay and electron microscopy by negative staining demonstrated laminin to have a concentration-dependent inhibitory effect on A β 42 Fibril Formation. The amyloid Fibril Formation was inhibited approximately by 70% due to the presence of 1.0 mg/ml laminin co-incubated with 1.0 mg/ml A β 42 peptide (molar ratio; A β 42 peptide:laminin=200:1). These results thus suggested that laminin or its derivatives may be effective as therapeutic agents to either prevent or slow down the progression of amyloidogenesis in Alzheimer's disease.
Anders Aspberg - One of the best experts on this subject based on the ideXlab platform.
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the tyrosine sulfate domain of fibromodulin binds collagen and enhances Fibril Formation
Journal of Biological Chemistry, 2016Co-Authors: Viveka Tillgren, Matthias Mörgelin, Patrik Onnerfjord, Sebastian Kalamajski, Anders AspbergAbstract:Small leucine-rich proteoglycans interact with other extracellular matrix proteins and are important regulators of matrix assembly. Fibromodulin has a key role in connective tissues, binding collagen through two identified binding sites in its leucine-rich repeat domain and regulating collagen Fibril Formation in vitro and in vivo Some nine tyrosine residues in the fibromodulin N-terminal domain are O-sulfated, a posttranslational modification often involved in protein interactions. The N-terminal domain mimics heparin, binding proteins with clustered basic amino acid residues. Because heparin affects collagen Fibril Formation, we investigated whether tyrosine sulfate is involved in fibromodulin interactions with collagen. Using full-length fibromodulin and its N-terminal tyrosine-sulfated domain purified from tissue, as well as recombinant fibromodulin fragments, we found that the N-terminal domain binds collagen. The tyrosine-sulfated domain and the leucine-rich repeat domain both bound to three specific sites along the collagen type I molecule, at the N terminus and at 100 and 220 nm from the N terminus. The N-terminal domain shortened the collagen Fibril Formation lag phase and tyrosine sulfation was required for this effect. The isolated leucine-rich repeat domain inhibited the Fibril Formation rate, and full-length fibromodulin showed a combination of these effects. The Fibrils formed in the presence of fibromodulin or its fragments showed more organized structure. Fibromodulin and its tyrosine sulfate domain remained bound on the formed fiber. Taken together, this suggests a novel, regulatory function for tyrosine sulfation in collagen interaction and control of Fibril Formation. (Less)
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The Tyrosine Sulfate Domain of Fibromodulin Binds Collagen and Enhances Fibril Formation.
The Journal of biological chemistry, 2016Co-Authors: Viveka Tillgren, Matthias Mörgelin, Patrik Onnerfjord, Sebastian Kalamajski, Anders AspbergAbstract:Small leucine-rich proteoglycans interact with other extracellular matrix proteins and are important regulators of matrix assembly. Fibromodulin has a key role in connective tissues, binding collagen through two identified binding sites in its leucine-rich repeat domain and regulating collagen Fibril Formation in vitro and in vivo Some nine tyrosine residues in the fibromodulin N-terminal domain are O-sulfated, a posttranslational modification often involved in protein interactions. The N-terminal domain mimics heparin, binding proteins with clustered basic amino acid residues. Because heparin affects collagen Fibril Formation, we investigated whether tyrosine sulfate is involved in fibromodulin interactions with collagen. Using full-length fibromodulin and its N-terminal tyrosine-sulfated domain purified from tissue, as well as recombinant fibromodulin fragments, we found that the N-terminal domain binds collagen. The tyrosine-sulfated domain and the leucine-rich repeat domain both bound to three specific sites along the collagen type I molecule, at the N terminus and at 100 and 220 nm from the N terminus. The N-terminal domain shortened the collagen Fibril Formation lag phase and tyrosine sulfation was required for this effect. The isolated leucine-rich repeat domain inhibited the Fibril Formation rate, and full-length fibromodulin showed a combination of these effects. The Fibrils formed in the presence of fibromodulin or its fragments showed more organized structure. Fibromodulin and its tyrosine sulfate domain remained bound on the formed fiber. Taken together, this suggests a novel, regulatory function for tyrosine sulfation in collagen interaction and control of Fibril Formation.
Geoffrey J. Howlett - One of the best experts on this subject based on the ideXlab platform.
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Shear Flow Induced Changes in Apolipoprotein C-II ConFormation and Amyloid Fibril Formation
Biochemistry, 2011Co-Authors: Chai Lean Teoh, Innocent B. Bekard, Peter Asimakis, Michael D. W. Griffin, Timothy M. Ryan, David E Dunstan, Geoffrey J. HowlettAbstract:The misfolding and self-assembly of proteins into amyloid Fibrils that occur in several debilitating diseases are affected by a variety of environmental factors, including mechanical factors associated with shear flow. We examined the effects of shear flow on amyloid Fibril Formation by human apolipoprotein C-II (apoC-II). Shear fields (150, 300, and 500 s–1) accelerated the rate of apoC-II Fibril Formation (1 mg/mL) approximately 5–10-fold. Fibrils produced at shear rates of 150 and 300 s–1 were similar to the twisted ribbon Fibrils formed in the absence of shear, while at 500 s–1, tangled ropelike structures were observed. The mechanism of the shear-induced acceleration of amyloid Fibril Formation was investigated at low apoC-II concentrations (50 μg/mL) where Fibril Formation does not occur. Circular dichroism and tryptophan fluorescence indicated that shear induced an irreversible change in apoC-II secondary structure. Fluorescence resonance energy transfer experiments using the single tryptophan resi...
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Apolipoproteins and amyloid Fibril Formation in atherosclerosis
Protein & Cell, 2011Co-Authors: Chai Lean Teoh, Michael D. W. Griffin, Geoffrey J. HowlettAbstract:Amyloid Fibrils arise from the aggregation of misfolded proteins into highly-ordered structures. The accumulation of these Fibrils along with some non-Fibrillar constituents within amyloid plaques is associated with the pathogenesis of several human degenerative diseases. A number of plasma apolipoproteins, including apolipoprotein (apo) A-I, apoA-II, apoC-II and apoE are implicated in amyloid Formation or influence amyloid Formation by other proteins. We review present knowledge of amyloid Formation by apolipoproteins in disease, with particular focus on atherosclerosis. Further insights into the molecular mechanisms underlying their amyloidogenic propensity are obtained from in vitro studies which describe factors affecting apolipoprotein amyloid Fibril Formation and interactions. Additionally, we outline the evidence that amyloid Fibril Formation by apolipoproteins might play a role in the development and progression of atherosclerosis, and highlight possible molecular mechanisms that could contribute to the pathogenesis of this disease.
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Lipids enhance apolipoprotein C-II-derived amyloidogenic peptide oligomerization but inhibit Fibril Formation
Journal of Physical Chemistry B, 2009Co-Authors: Andrew Hung, Geoffrey J. Howlett, Michael D. W. Griffin, Irene YarovskyAbstract:We investigated the effect of submicellar lipids on amyloid Fibril Formation. Thioflavin T fluorescence studies showed that submicellar levels of the short-chain phospholipids, dipentanoylphosphatidylcholine and dihexanoylphosphatidylcholine, strongly in inhibited amyloid Fibril Formation by an 11-residue peptide derived from human apolipoprotein C-II (apoC-II60?70). In contrast, sedimentation equilibrium analysis of these peptide?lipid mixtures indicated the presence of soluble oligomeric complexes. To acquire insight into the atomic level influences of these lipids on the initial stages of aggregation of the peptide, we performed molecular dynamics (MD) simulations coupled with umbrella sampling to determine dimerization free energies of a number of ?-stranded and random coil dimer complexes, both in the presence and absence of lipids. The simulations indicate that, in contrast to their inhibitory effects on Fibril Formation, short-chain phospholipids promote the Formation and stabilization of dimers by enhancing intersubunit hydrophobic interactions. On the basis of these experimental and computational results, we propose that peptide-bound lipids can inhibit amyloid Fibril Formation by trapping of dimers and other oligomeric species in diverse nonFibril forming conFormations, reducing their likelihood of acquiring subunit conFormations prone to Fibril nucleation and growth. In light of the demonstrated cytotoxicity of amyloid peptide oligomers, our results suggest that, by enhancing the stability of oligomeric peptide species, the presence of solvated lipids may contribute to the cytotoxicity of Fibrillogenic proteins and peptides.
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Fluorescence Detection of a Lipid-induced Tetrameric Intermediate in Amyloid Fibril Formation by Apolipoprotein C-II
Journal of Biological Chemistry, 2008Co-Authors: Timothy M. Ryan, Geoffrey J. Howlett, Michael F. BaileyAbstract:The misfolding and self-assembly of proteins into amyloid Fibrils that occurs in several debilitating and age-related diseases is affected by common components of amyloid deposits, notably lipids and lipid complexes. We have examined the effect of the short-chain phospholipids, dihexanoylphosphatidylcholine (DHPC) and dihexanoylphosphatidylserine (DHPS), on amyloid Fibril Formation by human apolipoprotein C-II (apoC-II). Micellar DHPC and DHPS strongly inhibited apoC-II Fibril Formation, whereas submicellar levels of these lipids accelerated apoC-II Fibril Formation to a similar degree. These results indicate that the net negative charge on DHPS, compared with the neutrally charged DHPC, is not critical for either the inhibition or activation process. We also investigated the mechanism for the submicellar, lipid-induced activation of Fibril Formation. Emission data for fluorescently labeled apoC-II indicated that DHPC and DHPS stimulate the early Formation and accumulation of oligomeric species. Sedimentation velocity and equilibrium experiments using a new fluorescence detection system identified a discrete lipid-induced tetramer formed at low apoC-II concentrations in the absence of significant Fibril Formation. Seeding experiments showed that this tetramer was on the Fibril-forming pathway. Fluorescence resonance energy transfer experiments established that this tetramer forms rapidly and is stabilized by submicellar, but not micellar, concentrations of DHPC and DHPS. Several recent studies show that oligomeric intermediates in amyloid Fibril Formation are toxic. Our results indicate that lipids promote on-pathway intermediates of apoC-II Fibril assembly and that the accumulation of a discrete tetrameric intermediate depends on the molecular state of the lipid.
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Fluorescence Detection of a Lipid-induced Tetrameric Intermediate in Amyloid Fibril Formation by Apolipoprotein C-II
Journal of Biological Chemistry, 2008Co-Authors: Timothy M. Ryan, Geoffrey J. Howlett, Michael F. BaileyAbstract:The misfolding and self-assembly of proteins into amyloid Fibrils that occurs in several debilitating and age-related diseases is affected by common components of amyloid deposits, notably lipids and lipid complexes. We have examined the effect of the short-chain phospholipids, dihexanoylphosphatidylcholine (DHPC) and dihexanoylphosphatidylserine (DHPS), on amyloid Fibril Formation by human apolipoprotein C-II (apoC-II). Micellar DHPC and DHPS strongly inhibited apoC-II Fibril Formation, whereas submicellar levels of these lipids accelerated apoC-II Fibril Formation to a similar degree. These results indicate that the net negative charge on DHPS, compared with the neutrally charged DHPC, is not critical for either the inhibition or activation process. We also investigated the mechanism for the submicellar, lipid-induced activation of Fibril Formation. Emission data for fluorescently labeled apoC-II indicated that DHPC and DHPS stimulate the early Formation and accumulation of oligomeric species. Sedimentation velocity and equilibrium experiments using a new fluorescence detection system identified a discrete lipid-induced tetramer formed at low apoC-II concentrations in the absence of significant Fibril Formation. Seeding experiments showed that this tetramer was on the Fibril-forming pathway. Fluorescence resonance energy transfer experiments established that this tetramer forms rapidly and is stabilized by submicellar, but not micellar, concentrations of DHPC and DHPS. Several recent studies show that oligomeric intermediates in amyloid Fibril Formation are toxic. Our results indicate that lipids promote on-pathway intermediates of apoC-II Fibril assembly and that the accumulation of a discrete tetrameric intermediate depends on the molecular state of the lipid.
Akira Monji - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Aβ Fibril Formation and Aβ-induced cytotoxicity by senile plaque-associated proteins
Neuroscience Letters, 2000Co-Authors: Akira Monji, Ichiro Yoshida, Ken-ichiro Tashiro, Yoshihito Hayashi, Kazunori Matsuda, Nobutada TashiroAbstract:Aβ neurotoxicity is generally believed to require Aβ Fibril Formation. The prevention of Aβ Fibril Formation thus seems to be a promising strategy for the treatment of AD. Recent studies have shown senile plaque-associated proteins such as laminin to have an inhibitory effect on both Aβ40 and Aβ42 Fibril Formation in vitro. In the present study, we thus investigated whether or not midkine (MK) and α2-macroglobulin (α2M), both of which are also senile plaque-associated proteins like laminin, affect Aβ Fibril Formation and Aβ-induced cytotoxicity. The present study demonstrated that both MK and α2M inhibit both Aβ Fibril Formation and Aβ-induced cytotoxicity in PC12 cells. The confirmation of the present results based on in vivo experiments is called for in future studies to clarify whether or not senile plaque-associated proteins such as MK and α2M can be a model for therapeutic agents in the treatment of AD.
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Inhibition of A beta Fibril Formation and A beta-induced cytotoxicity by senile plaque-associated proteins.
Neuroscience letters, 2000Co-Authors: Akira Monji, Ichiro Yoshida, Yoshihito Hayashi, Kazunori Matsuda, K Tashiro, Nobutada TashiroAbstract:A beta neurotoxicity is generally believed to require A beta Fibril Formation. The prevention of A beta Fibril Formation thus seems to be a promising strategy for the treatment of AD. Recent studies have shown senile plaque-associated proteins such as laminin to have an inhibitory effect on both A beta40 and A beta42 Fibril Formation in vitro. In the present study, we thus investigated whether or not midkine (MK) and alpha2-macroglobulin (alpha2M), both of which are also senile plaque-associated proteins like laminin, affect A beta Fibril Formation and A beta-induced cytotoxicity. The present study demonstrated that both MK and alpha2M inhibit both A beta Fibril Formation and A beta-induced cytotoxicity in PC12 cells. The confirmation of the present results based on in vivo experiments is called for in future studies to clarify whether or not senile plaque-associated proteins such as MK and alpha2M can be a model for therapeutic agents in the treatment of AD.
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Laminin inhibits Aβ40 Fibril Formation promoted by apolipoprotein E4 in vitro
Brain Research, 1998Co-Authors: Akira Monji, Ichiro Yoshida, Ken-ichiro Tashiro, Yoshihito Hayashi, Nobutada TashiroAbstract:Abstract The aggregation of soluble Aβ into insoluble amyloid Fibrils is believed to be an important step in the pathogenesis of Alzheimer's disease (AD) and the prevention of this process therefore seems to be a promising strategy for the treatment of AD. Both apolipoprotein E(apoE) and laminin are known to play important roles in the regeneration of the central nervous system and both are known to accumulate in the senile plaques of the AD brains. In the present study, we therefore investigated whether or not laminin has any effect on Aβ40 Fibril Formation promoted by apoE4 in vitro. A thioflavine-T fluorometric assay and electron microscopic observations using negative staining together demonstrated that laminin inhibits Aβ40 Fibril Formation in vitro while it also inhibits Aβ40 Fibril Formation promoted by apoE4. These results suggested that either laminin or its derivatives may thus be effective as therapeutic agents for AD.
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Laminin inhibits A beta 40 Fibril Formation promoted by apolipoprotein E4 in vitro.
Brain research, 1998Co-Authors: Akira Monji, K Tashiro, I Yoshida, Y Hayashi, N TashiroAbstract:The aggregation of soluble A beta into insoluble amyloid Fibrils is believed to be an important step in the pathogenesis of Alzheimer's disease (AD) and the prevention of this process therefore seems to be a promising strategy for the treatment of AD. Both apolipoprotein E(apoE) and laminin are known to play important roles in the regeneration of the central nervous system and both are known to accumulate in the senile plaques of the AD brains. In the present study, we therefore investigated whether or not laminin has any effect on A beta 40 Fibril Formation promoted by apoE4 in vitro. A thioflavine-T fluorometric assay and electron microscopic observations using negative staining together demonstrated that laminin inhibits A beta 40 Fibril Formation in vitro while it also inhibits A beta 40 Fibril Formation promoted by apoE4. These results suggested that either laminin or its derivatives may thus be effective as therapeutic agents for AD.
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Laminin inhibits Abeta42 Fibril Formation in vitro.
Brain research, 1998Co-Authors: Akira Monji, K Tashiro, I Yoshida, N TashiroAbstract:In the present study, we investigated whether or not laminin inhibits Abeta42 Fibril Formation in the same manner as Abeta40. Both a thioflavine-T fluorometric assay and electron microscopy by negative staining demonstrated laminin to have a concentration-dependent inhibitory effect on Abeta42 Fibril Formation. The amyloid Fibril Formation was inhibited approximately by 70% due to the presence of 1.0 mg/ml laminin co-incubated with 1. 0 mg/ml Abeta42 peptide (molar ratio; Abeta42 peptide:laminin=200:1). These results thus suggested that laminin or its derivatives may be effective as therapeutic agents to either prevent or slow down the progression of amyloidogenesis in Alzheimer's disease.