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Virginia M Y Lee - One of the best experts on this subject based on the ideXlab platform.
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thromboxane receptor activation mediates isoprostane induced increases in amyloid pathology in tg2576 mice
The Journal of Neuroscience, 2008Co-Authors: Diana W Shineman, Domenico Pratico, Bin Zhang, Susan Leight, Virginia M Y LeeAbstract:Alzheimer's disease (AD) amyloid plaques are composed of amyloid-beta (Abeta) peptides produced from proteolytic cleavage of amyloid precursor protein (APP). Isoprostanes, markers of in vivo oxidative stress, are elevated in AD patients and in the Tg2576 mouse model of AD-like Abeta brain pathology. To determine whether isoprostanes increase Abeta production, we delivered isoprostane iPF(2alpha)-III into the brains of Tg2576 mice. Although treated mice showed increased brain Abeta levels and plaque-like deposits, this was blocked by a thromboxane (TP) receptor antagonist, suggesting that TP receptor activation mediates the effects of iPF(2alpha)-III on Abeta. This hypothesis was supported by cell culture studies that showed that TP receptor activation increased Abeta and secreted APP ectodomains. This increase was a result of increased APP mRNA stability leading to elevated APP mRNA and protein levels. The increased APP provides more substrate for alpha and beta secretase proteolytic cleavages, thereby increasing Abeta generation and amyloid plaque deposition. To test the effectiveness of targeting the TP receptor for AD therapy, Tg2576 mice underwent long-term treatment with S18886, an orally available TP receptor antagonist. S18886 treatment reduced amyloid plaques, insoluble Abeta, and APP levels, thereby implicating TP receptor signaling as a novel target for AD therapy.
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targeting amyloid β peptide aβ oligomers by passive immunization with a conformation selective monoclonal antibody improves learning and memory in aβ precursor protein app transgenic mice
Journal of Biological Chemistry, 2006Co-Authors: Edward B Lee, Bin Zhang, Lewis Leng, Linda Kwong, John Q Trojanowski, Ted Abel, Virginia M Y LeeAbstract:Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid-beta peptide (Abeta) levels and improves cognitive function. To specifically address the role of Abeta oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order Abeta structures but not full-length amyloid-beta precursor protein or C-terminal amyloid-beta precursor protein fragments. NAB61 also recognized a subset of brain Abeta deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated Abeta oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.
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targeting amyloid beta peptide abeta oligomers by passive immunization with a conformation selective monoclonal antibody improves learning and memory in abeta precursor protein app transgenic mice
Journal of Biological Chemistry, 2006Co-Authors: Edward B Lee, Bin Zhang, Lewis Leng, Linda Kwong, John Q Trojanowski, Ted Abel, Virginia M Y LeeAbstract:Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid-beta peptide (Abeta) levels and improves cognitive function. To specifically address the role of Abeta oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order Abeta structures but not full-length amyloid-beta precursor protein or C-terminal amyloid-beta precursor protein fragments. NAB61 also recognized a subset of brain Abeta deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated Abeta oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.
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environmental enrichment reduces aβ levels and amyloid deposition in transgenic mice
Cell, 2005Co-Authors: Orly Lazarov, Virginia M Y Lee, John E Robinson, Yaping Tang, Ilana S Hairston, Zeljka Korademirnics, Louis B Hersh, Robert M Sapolsky, Karoly Mirnics, Sangram S. SisodiaAbstract:Cerebral deposition of Beta-Amyloid (Abeta) peptides is an invariant pathological hallmark in brains of patients with Alzheimer's disease (AD) and transgenic mice coexpressing familial AD-linked APP and PS1 variants. We now report that exposure of transgenic mice to an "enriched environment" results in pronounced reductions in cerebral Abeta levels and amyloid deposits, compared to animals raised under "standard housing" conditions. The enzymatic activity of an Abeta-degrading endopeptidase, neprilysin, is elevated in the brains of "enriched" mice and inversely correlated with amyloid burden. Moreover, DNA microarray analysis revealed selective upregulation in levels of transcripts encoded by genes associated with learning and memory, vasculogenesis, neurogenesis, cell survival pathways, Abeta sequestration, and prostaglandin synthesis. These studies provide evidence that environmental enrichment leads to reductions in steady-state levels of cerebral Abeta peptides and amyloid deposition and selective upregulation in levels of specific transcripts in brains of transgenic mice.
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gsk 3α regulates production of alzheimer s disease amyloid β peptides
Nature, 2003Co-Authors: Christopher J Phiel, Christina A Wilson, Virginia M Y Lee, Peter S KleinAbstract:Alzheimer's disease is associated with increased production and aggregation of amyloid-beta (Abeta) peptides. Abeta peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE, followed by presenilin-dependent gamma-secretase cleavage. Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for gamma-secretase function. Presenilins also interact with alpha-catenin, beta-catenin and glycogen synthase kinase-3beta (GSK-3beta), but a functional role for these proteins in gamma-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor, block the production of Abeta peptides by interfering with APP cleavage at the gamma-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Abeta peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease.
Christer Nordstedt - One of the best experts on this subject based on the ideXlab platform.
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controlling amyloid β peptide fibril formation with protease stable ligands
Journal of Biological Chemistry, 1997Co-Authors: Lars O. Tjernberg, Lars Terenius, Johan Thyberg, Jan Naslund, Christina Lilliehook, David J E Callaway, Solveig Hahne, Christer NordstedtAbstract: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., Naslund, J., Lindqvist, F., Johansson, J., Karlstrom, 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.
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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.
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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: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.
Edward B Lee - One of the best experts on this subject based on the ideXlab platform.
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targeting amyloid β peptide aβ oligomers by passive immunization with a conformation selective monoclonal antibody improves learning and memory in aβ precursor protein app transgenic mice
Journal of Biological Chemistry, 2006Co-Authors: Edward B Lee, Bin Zhang, Lewis Leng, Linda Kwong, John Q Trojanowski, Ted Abel, Virginia M Y LeeAbstract:Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid-beta peptide (Abeta) levels and improves cognitive function. To specifically address the role of Abeta oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order Abeta structures but not full-length amyloid-beta precursor protein or C-terminal amyloid-beta precursor protein fragments. NAB61 also recognized a subset of brain Abeta deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated Abeta oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.
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targeting amyloid beta peptide abeta oligomers by passive immunization with a conformation selective monoclonal antibody improves learning and memory in abeta precursor protein app transgenic mice
Journal of Biological Chemistry, 2006Co-Authors: Edward B Lee, Bin Zhang, Lewis Leng, Linda Kwong, John Q Trojanowski, Ted Abel, Virginia M Y LeeAbstract:Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid-beta peptide (Abeta) levels and improves cognitive function. To specifically address the role of Abeta oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order Abeta structures but not full-length amyloid-beta precursor protein or C-terminal amyloid-beta precursor protein fragments. NAB61 also recognized a subset of brain Abeta deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated Abeta oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.
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secretion and intracellular generation of truncated aβ in β site amyloid β precursor protein cleaving enzyme expressing human neurons
Journal of Biological Chemistry, 2003Co-Authors: Edward B Lee, Daniel M Skovronsky, Farhad Abtahian, Robert W Doms, Virginia M Y LeeAbstract:Insoluble pools of the amyloid-beta peptide (Abeta) in brains of Alzheimer's disease patients exhibit considerable N- and C-terminal heterogeneity. Mounting evidence suggests that both C-terminal extensions and N-terminal truncations help precipitate amyloid plaque formation. Although mechanisms underlying the increased generation of C-terminally extended peptides have been extensively studied, relatively little is known about the cellular mechanisms underlying production of N-terminally truncated Abeta. Thus, we used human NT2N neurons to investigate the production of Abeta11-40/42 from amyloid-beta precursor protein (APP) by beta-site APP-cleaving enzyme (BACE). When comparing undifferentiated human embryonal carcinoma NT2- cells and differentiated NT2N neurons, the secretion of sAPP and Abeta correlated with BACE expression. To study the effects of BACE expression on endogenous APP metabolism in human cells, we overexpressed BACE in undifferentiated NT2- cells and NT2N neurons. Whereas NT2N neurons produced both full-length and truncated Abeta as a result of normal processing of endogenous APP, BACE overexpression increased the secretion of Abeta1-40/42 and Abeta11-40/42 in both NT2- cells and NT2N neurons. Furthermore, BACE overexpression resulted in increased intracellular Abeta1-40/42 and Abeta11-40/42. Therefore, we conclude that Abeta11-40/42 is generated prior to deposition in senile plaques and that N-terminally truncated Abeta peptides may contribute to the downstream effects of amyloid accumulation in Alzheimer's disease.
Lars O. Tjernberg - One of the best experts on this subject based on the ideXlab platform.
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controlling amyloid β peptide fibril formation with protease stable ligands
Journal of Biological Chemistry, 1997Co-Authors: Lars O. Tjernberg, Lars Terenius, Johan Thyberg, Jan Naslund, Christina Lilliehook, David J E Callaway, Solveig Hahne, Christer NordstedtAbstract: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., Naslund, J., Lindqvist, F., Johansson, J., Karlstrom, 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.
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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.
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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: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.
Ruth Nussinov - One of the best experts on this subject based on the ideXlab platform.
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stabilities and conformations of alzheimer s β amyloid peptide oligomers aβ16 22 aβ16 35 and aβ10 35 sequence effects
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Ruth NussinovAbstract:Previously, we have studied the minimal oligomer size of an aggregate amyloid seed and the mechanism of seed growth with a multilayer beta-sheet model. Under high temperature simulation conditions, our approach can test the stability of possible amyloid forms. Here, we report our study of oligomers of Alzheimer's amyloid beta-peptide (Abeta) fragments 16-22, 16-35, and 10-35 (abbreviated Abeta(16-22), Abeta(16-35), and Abeta(10-35), respectively). Our simulations indicate that an antiparallel beta-sheet orientation is the most stable for the Abeta(16-22), in agreement with a solid state NMR-based model [Balbach, J. J., Ishii, Y., Antzutkin, O. N., Leapman, R. D., Rizzo, N. W., et al. (2000) Biochemistry 39, 13748-13759]. A model with twenty-four Abeta(16-22) strands indicates a highly twisted fibril. Whereas the short Abeta(16-22) and Abeta(24-36) may exist in fully extended form, the linear parallel beta-sheets for Abeta(16-35) appear impossible, mainly because of the polar region in the middle of the 16-35 sequence. However, a bent double-layered hairpin-like structure (called hook) with the polar region at the turn forms parallel beta-sheets with higher stability. An intra-strand salt-bridge (D23-K28) stabilizes the bent hairpin-like hook structure. The bent double-beta-sheet model for the Abeta(10-35) similarly offers oligomer stability.
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stabilities and conformations of alzheimer s beta amyloid peptide oligomers abeta 16 22 abeta 16 35 and abeta 10 35 sequence effects
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Ruth NussinovAbstract:Previously, we have studied the minimal oligomer size of an aggregate amyloid seed and the mechanism of seed growth with a multilayer beta-sheet model. Under high temperature simulation conditions, our approach can test the stability of possible amyloid forms. Here, we report our study of oligomers of Alzheimer's amyloid beta-peptide (Abeta) fragments 16-22, 16-35, and 10-35 (abbreviated Abeta(16-22), Abeta(16-35), and Abeta(10-35), respectively). Our simulations indicate that an antiparallel beta-sheet orientation is the most stable for the Abeta(16-22), in agreement with a solid state NMR-based model [Balbach, J. J., Ishii, Y., Antzutkin, O. N., Leapman, R. D., Rizzo, N. W., et al. (2000) Biochemistry 39, 13748-13759]. A model with twenty-four Abeta(16-22) strands indicates a highly twisted fibril. Whereas the short Abeta(16-22) and Abeta(24-36) may exist in fully extended form, the linear parallel beta-sheets for Abeta(16-35) appear impossible, mainly because of the polar region in the middle of the 16-35 sequence. However, a bent double-layered hairpin-like structure (called hook) with the polar region at the turn forms parallel beta-sheets with higher stability. An intra-strand salt-bridge (D23-K28) stabilizes the bent hairpin-like hook structure. The bent double-beta-sheet model for the Abeta(10-35) similarly offers oligomer stability.