Direct visualisation of the β-sheet structure of synthetic Alzheimer’s amyloid 1 1Edited by F. E. Cohen

Serpell, Louise C.; Smith, Judith M.

doi:10.1006/jmbi.2000.3650

Cited by 173 publications

(123 citation statements)

References 37 publications

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“…This result is similar to the previous results by Liu et al [12], which indicated that residues 17-20 and 30-35 were the important regions for promoting Ab aggregation. The formation of b-sheet conformation has been proposed to be the key step for Ab aggregation [22,24], however, the propensity to form bsheets by the truncated Ab peptides did not fully correspond to the neurotoxicity and aggregative ability hierarchy, as the 25-35 truncated peptides adopted a greater proportion of bsheets than the other truncated peptides, including the 36-40 truncated Ab peptides. Besides, the IC 50 value of Ab17-35, which lacks the N-terminal residues 1-16, is $300 lM that is higher than those of the 17-21, 22-24 and 25-35 truncated Ab peptides.…”

Section: Discussionmentioning

confidence: 99%

The correlation between neurotoxicity, aggregative ability and secondary structure studied by sequence truncated Aβ peptides

et al. 2007

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Aggregated b-amyloid (Ab) peptides are neurotoxic and cause neuronal death both in vitro and in vivo. Although the formation of a b-sheet structure is usual required to form aggregates, the relationship between neurotoxicity and the Ab sequence remains unclear. To explore the correlation between Ab sequence, secondary structure, aggregative ability, and neurotoxicity, we utilized both full-length and fragment-truncated Ab peptides. Using a combination of spectroscopic and cellular techniques, we demonstrated that neurotoxicity and aggregative ability are correlated while the relationship between these characteristics and secondary structure is not significant. The hydrophobic C-terminus, particularly the amino acids of 17-21, 25-35, and 41-42, is the main region responsible for neurotoxicity and aggregation. Deleting residues 17-21, 25-35 or 41-42 significantly reduced the toxicity. On the other hand, truncation of the peptides at either residues 22-24 or residues 36-40 had little effect on toxicity and aggregative ability. While the N-terminal residues 1-16 may not play a major role in neurotoxicity and aggregation, a lack of N-terminal fragment Ab peptide, (e.g. Ab17-35), does not display the neurotoxicity of either full-length or 17-21, 25-35 truncated Ab peptides.

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Section: Discussionmentioning

confidence: 99%

The correlation between neurotoxicity, aggregative ability and secondary structure studied by sequence truncated Aβ peptides

et al. 2007

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“…For instance, conformational changes in ␤-amyloid (A␤) in Alzheimer disease and ␣-synuclein in Parkinson disease lead to the formation of abnormal oligomers and amyloid fibrils (8). Similar to A␤ and ␣-synuclein, GAPDH is also amyloidogenic (9 -14).…”

Section: Glyceraldehyde-3-phosphate Dehydrogenase (Gapdh)mentioning

confidence: 99%

Glyceraldehyde-3-phosphate Dehydrogenase Aggregate Formation Participates in Oxidative Stress-induced Cell Death

Nakajima

Amano

Kubo

et al. 2009

Journal of Biological Chemistry

125

123

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)2 is a classic glycolytic enzyme that also mediates cell death by its nuclear translocation under oxidative stress. Meanwhile, we previously presented that oxidative stress induced disulfide-bonded GAPDH aggregation in vitro. Here, we propose that GAPDH aggregate formation might participate in oxidative stress-induced cell death both in vitro and in vivo. We show that human GAPDH amyloidlike aggregate formation depends on the active site cysteine-152 (Cys-152) in vitro. In SH-SY5Y neuroblastoma, treatment with dopamine decreases the cell viability concentration-dependently (IC 50 ‫؍‬ 202 M). Low concentrations of dopamine (50 -100 M) mainly cause nuclear translocation of GAPDH, whereas the levels of GAPDH aggregates correlate with high concentrations of dopamine (200 -300 M)-induced cell death. Doxycycline-inducible overexpression of wild-type GAPDH in SH-SY5Y, but not the Cys-152-substituted mutant (C152A-GAPDH), accelerates cell death accompanying both endogenous and exogenous GAPDH aggregate formation in response to high concentrations of dopamine. Deprenyl, a blocker of GAPDH nuclear translocation, fails to inhibit the aggregation both in vitro and in cells but reduced cell death in SH-SY5Y treated with only a low concentration of dopamine (100 M). These results suggest that GAPDH participates in oxidative stress-induced cell death via an alternative mechanism in which aggregation but not nuclear translocation of GAPDH plays a role. Moreover, we observe endogenous GAPDH aggregate formation in nigra-striatum dopaminergic neurons after methamphetamine treatment in mice. In transgenic mice overexpressing wildtype GAPDH, increased dopaminergic neuron loss and GAPDH aggregate formation are observed. These data suggest a critical role of GAPDH aggregates in oxidative stress-induced brain damage.Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classic glycolytic enzyme that is also involved in cell death and neuropsychiatric conditions (1, 2). GAPDH mediates cell death under oxidative stress conditions at least in part through nuclear translocation together with Siah (3). In the nucleus, GAPDH activates p300/CBP and regulates gene transcription (4). The pathway can be blocked by deprenyl (Selegiline), a neuroprotective compound (5). Although nuclear translocation of GAPDH is known to cause cell death, other mechanisms of GAPDH-associated cell death may also exist.Several neurodegenerative diseases are characterized by the accumulation of misfolded proteins, resulting in intracellular and extracellular protein aggregates (6, 7). For instance, conformational changes in ␤-amyloid (A␤) in Alzheimer disease and ␣-synuclein in Parkinson disease lead to the formation of abnormal oligomers and amyloid fibrils (8). Similar to A␤ and ␣-synuclein, GAPDH is also amyloidogenic (9 -14). We previously reported the molecular mechanism underlying oxidative stressinduced amyloid-like aggregation of GAPDH using the purified rabbit GAPDH and demonstrated the critical role of the act...

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“…From the standpoint of molecular structure, the defining feature of an amyloid fibril is the presence of cross-β supramolecular structure, meaning that the β-sheets within the fibril are formed by β-strand segments that run approximately perpendicular to the long axis of the fibril and are linked by hydrogen bonds that run approximately parallel to this axis (11)(12)(13). Although determination of the molecular structures of amyloid fibrils is made difficult by their inherent noncrystallinity and insolubility, techniques such as solid state nuclear magnetic resonance (NMR) (12,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), electron paramagnetic resonance (EPR) (34)(35)(36), electron microscopy (37)(38)(39)(40)(41)(42)(43), hydrogen/deuterium exchange (29,(44)(45)(46)(47), scanning mutagenesis (48), chemical crosslinking (27,49,50), and x-ray diffraction of amyloid-like crystals …”

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confidence: 99%

Peptide Conformation and Supramolecular Organization in Amylin Fibrils: Constraints from Solid-State NMR

et al. 2007

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The 37-residue amylin peptide, also known as islet amyloid polypeptide, forms fibrils that are the main peptide or protein component of amyloid that develops in the pancreas of type 2 diabetes patients. Amylin also readily forms amyloid fibrils in vitro that are highly polymorphic under typical experimental conditions. We describe a protocol for the preparation of synthetic amylin fibrils that exhibit a single predominant morphology, which we call a striated ribbon, in electron microscope and atomic force microscope images. Solid state nuclear magnetic resonance (NMR) measurements on a series of isotopically labeled samples indicate a single molecular structure within the striated ribbons. We use scanning transmission electron microscopy and several types of one-dimensional and two-dimensional solid state NMR techniques to obtain constraints on the peptide conformation and supramolecular structure in these amylin fibrils, and derive molecular structural models that are consistent with the experimental data. The basic structural unit in amylin striated ribbons, which we call the protofilament, contains four-layers of parallel β-sheets, formed by two symmetric layers of amylin molecules. The molecular structure of amylin protofilaments in striated ribbons closely resembles the protofilament in amyloid fibrils with similar morphology formed by the 40-residue β-amyloid peptide that is associated with Alzheimer's disease. Keywordsislet amyloid polypeptide; type 2 diabetes; amyloid fibril structure; electron microscopy; atomic force microscopy Amylin, also called islet amyloid polypeptide or IAPP, is a 37-residue peptide that is cosecreted with insulin by the β-cells of pancreas. The normal biological effects of amylin secretion include inhibition of glucagon secretion and reduction of the rate of gastric emptying, effects that contribute to the maintenance of postprandial glucose homeostasis (1). Amylin is the major peptide or protein component of the islet amyloid found in the pancreas of approximately 90% of type 2 (or non-insulin-dependent) diabetes patients (2,3). Fibrillar amylin has been shown * Corresponding author: Dr. Robert Tycko, National Institutes of Health, Building 5, Room 112, Bethesda, MD 20892-0520. phone 301-402-8272. fax 301-496-0825. e-mail robertty@mail.nih.gov.Supporting Information Available HPLC chromatograms from the purification of both reduced and oxidized amylin by reverse-phase chromatography ( Figure S1); FPLC chromatograms from the purification of both human and rodent amylin by size-exclusion chromatography ( Figure S2); 1D 13 C spectra of amylin fibrils with various isotopic labeling patterns, in lyophilized and rehydrated conditions ( Figures S3-S5); Table of 13 C NMR chemical shifts in amylin fibrils, TALOS predictions of backbone torsion angles based on these shifts, and torsion angles determined from 15 N fpRFDR-CT measurements (Table S1). This material is freely available on the World Wide Web at http://www.acs.org. to be toxic to cultured β-cells (4), and has been propo...

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Direct visualisation of the β-sheet structure of synthetic Alzheimer’s amyloid 1 1Edited by F. E. Cohen

Cited by 173 publications

References 37 publications

The correlation between neurotoxicity, aggregative ability and secondary structure studied by sequence truncated Aβ peptides

The correlation between neurotoxicity, aggregative ability and secondary structure studied by sequence truncated Aβ peptides

Glyceraldehyde-3-phosphate Dehydrogenase Aggregate Formation Participates in Oxidative Stress-induced Cell Death

Peptide Conformation and Supramolecular Organization in Amylin Fibrils: Constraints from Solid-State NMR

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