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Amyloid. 2000 Sep;7(3):194-9.
Amyloid peptide channels: blockade by zinc and inhibition by Congo red (amyloid channel block).

Hirakura Y, Yiu WW, Yamamoto A, Kagan BL.

Department of Psychiatry, Neuropsychiatric Institute, Brain Research Institute and Mental Retardation Research Center, UCLA School of Medicine and West Los Angeles VA Medical Center, CA, USA.

Amyloid peptides are the major constituents of amyloid deposits in various amyloid diseases including Alzheimer's disease, type II diabetes mellitus, prion diseases and others. The hallmark of amyloid is the binding of the dye, Congo red, which creates characteristic staining due to the dye's ability to bind the beta sheet aggregates referred to as amyloid. Previous reports have demonstrated that several cytotoxic, amyloidogenic peptides can form ion channels in planar phospholipid bilayer membranes and have suggested that these channels may represent the pathogenic mechanism of cell and tissue destruction in amyloid disease. Furthermore, zinc and Congo red can ameliorate or prevent the pathogenic effect of certain amyloidpeptides. We report here that zinc at micromolar concentrations caused a reversible blockade of islet amyloid polypeptide (IAPP, amylin) and PrP 106-126 channels whereas calcium and magnesium did not. Congo red completely inhibited channel formation if preincubated with amyloid peptides, but had no effect on IAPP or PrP 106-126 channels once formed. These results suggest a requirement for aggregation for the formation of amyloid peptide channels and are consistent with the "channel hypothesis" of amyloid disease. They also suggest potential avenues for ameliorative therapy of these illnesses.


PMID:_11019860



J Neurosci Res. 2000 Oct 15;62(2):293-301.
Amyloidogenicity and neurotoxicity of peptides corresponding to the helical regions of PrP(C).

Thompson A, White AR, McLean C, Masters CL, Cappai R, Barrow CJ.

School of Chemistry, The University of Melbourne, Parkville, Victoria, Australia.

An alpha-helical to beta-sheet conformational change in the prion protein, PrP(C), is believed to be causative in transmissible spongiform encephalopathies. Recent nuclear magnetic resonance structures of PrP(C) have identified three helical regions in the normal full-length protein. We have synthesised peptides corresponding to these helical regions (PrP144-154, helical region one; PrP178-193, helical region two; and PrP198-218, helical region three). Circular dichroism results show that the peptide corresponding to helical region one is unstructured, while peptides corresponding to the second and third helical regions have a high propensity to form beta-sheet structure in a pH-dependent manner in aqueous solutions. Peptides corresponding to the second helical region, PrP180-193 and PrP178-193, are the only ones that form amyloid by electron microscopy and congo red birefringence. PrP178-193 and the amyloidogenic Alzheimer's disease Abeta25-25 peptide were found to promote Cu (II)-induced lipid peroxidation and cytotoxicity in primary neuronal cultures, while PrP144-154, PrP198-218 and the nonamyloidogenic Abeta1-28 had no effect on Cu (II) toxicity. There was no increase in toxicity induced by PrP178-193 in cultures treated with Fe (II) or hydrogen peroxide, indicating a preferential modulatory effect on Cu (II) toxicity by PrP178-193. The data suggest that the PrP178-193 peptide has both structural and bioactive properties in common with Abeta25-35 and that the second putative helical region of PrP could be involved in modulation of Cu (II)-mediated toxicity in neurons during prion disease. 2000 Wiley-Liss, Inc.


PMID:_11020222



FEBS Lett. 2000 Oct 6;482(3):257-60.
Laminin-induced PC-12 cell differentiation is inhibited following laser inactivation of cellular prion protein.

Graner E, Mercadante AF, Zanata SM, Martins VR, Jay DG, Brentani RR.

Ludwig Institute for Cancer Research, Sao Paulo, Brazil.

Prions, the etiological agents for infectious degenerative encephalopathies, act by inducing structural modifications in the cellular prion protein (PrPc). Recently, we demonstrated that PrPc binds laminin (LN) and that this interaction is important for the neuritogenesis of cultured hippocampal neurons. Here we have used the PC-12 cell model to explore the biological role of LN-PrPc interaction. Antibodies against PrPc inhibit cell adhesion to LN-coated culture plaques. Furthermore, chromophore-assisted laser inactivation of cell surface PrPc perturbs LN-induced differentiation and promotes retraction of mature neurites. These results point out to the importance of PrPc as a cell surface ligand for LN.


PMID:_11024471



Ann Neurol. 2000 Oct;48(4):665-8.
Sporadic fatal insomnia: a case study.

Scaravilli F, Cordery RJ, Kretzschmar H, Gambetti P, Brink B, Fritz V, Temlett J, Kaplan C, Fish D, An SF, Schulz-Schaeffer WJ, Rossor MN.

Department of Neuropathology, Institute of Neurology, University College London, UK.

A 58-year-old man died after a 27-month illness characterized by insomnia, confirmed by polysomnography. He was homozygous for methionine at codon 129 of the prion gene but had no mutation in the prion gene. Neuropathology showed thalamic and olivary atrophy and no spongiform changes. Paraffin-embedded tissue blotting demonstrated abnormal prion protein in the brain. This is the first case of the sporadic form of fatal familial insomnia with demonstration of the disorder by polysomnography.


PMID:_11026452

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