Amyloidogenicity of rodent and human βA4 sequences

Dyrks, Thomas; Dyrks, Elke; Masters, Colin L.; Beyreuther, Konrad

doi:10.1016/0014-5793(93)81399-k

Cited by 175 publications

(123 citation statements)

References 30 publications

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“…Several reports have revealed that exogenous AR causes neuronal degeneration in primary cultured neurons (Yankner et [G1u22]AR1-28 peptide solution. Dyrks et al (1993) have shown that the aggregation of A/3 and the C-terminal amyloidogenic APP fragments depend on oxidation of His, Tyr and Met residues, and that the addition of radical scavengers prevents the aggregation process induced by metal-catalyzed oxidation systems (Dyrks et al 1992). The report that the iron homeostasis is disrupted in Alzheimer's disease brains (Kawamata et al 1993) may also supports the involvement of metal-catalyzed radical reactions in the aggregation process of AR (Dyrks et al 1992).…”

Section: Discussionmentioning

confidence: 99%

Racemization: Its Biological Significance on Neuropathogenesis of Alzheimer's Disease.

Mori

Ishii

Tomiyama

et al. 1994

Tohoku J. Exp. Med.

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Section: Discussionmentioning

confidence: 99%

Racemization: Its Biological Significance on Neuropathogenesis of Alzheimer's Disease.

Mori

Ishii

Tomiyama

et al. 1994

Tohoku J. Exp. Med.

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“…The exact amyloidogeni¢ mechanism by which pA4 is cleaved from APP and deposited in AD remains unknown, although our earlier [1] and reins studies [15] suggest that th¢ initial step of the abnormal processing of full-length APP in Alzheimer's disease may occur at the NH,.terminus of the 3A4 sequence and generate a COOH-terminal fragment of 100 residues (A4CT), which includes the amyloid pA4 sequence, and the transmembrane and cytoplasmic domains of all known transmembrane APP forms.…”

Section: L Introductionmentioning

confidence: 93%

Membrane inserted APP fragments containing the βA4 sequence of Alzheimer's disease do not aggregate

Dyrks

Masters

et al. 1992

FEBS Letters

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Previously w¢ have shown that the COOH.terminal fragment (A4CT) of flu= Ahhcimcr amyloid protein precursor (APP), which at the N H_.-tcrminus ¢arricl the ~quencc of the amyloid .8A4 protein, forms highly inrmluble aggre~tes [EMBO .I. (1988) 7. 949-957]. Here ~ report thai aggregation is prevented if A4CT is ¢xpreucd in vitro with tt signal ~=quenee at the NH:.terminus (SPA4CT) under conditions which allow membrane immrtion.Aglirellates from gPA4CT are obtained alter removal of membranes h)' chlorofon~methunol extraction or heating.A4CT; In vitro translation; AIIllrqlation; Alxheimer's disca~The histopathological features of Alzheimer's disease (AD) and the mechanisms underlying amyloid deposition in AD have been intensively investigated [2][3][4][5][6][7]. The isolation and sequence analysis of#A4 [3-6] from intra~llular and extracellalar amyloid in AD and Dawn's syndrome brains has led to the isolation and characterization of the family of amyloid protein precursors (APP's) as glycosylated, tyrosine-sulfated transmem. brane proteins [8][9][10][11][12], The ~A4 protein is encoded within the transmembrane and extracellular domains of the APP's [8].The normal route of APP processing involves cleavage of APP within the,aA4 sequence [12][13][14]. This suggests that the NHa-terminus of'the amyloid/~A4 protein is not produced by the normal cleavage which leads to shedding of the extraceliular part of cell-surface transmembrane APP's.The exact amyloidogeni¢ mechanism by which pA4 is cleaved from APP and deposited in AD remains unknown, although our earlier [1] and reins studies [15] suggest that th¢ initial step of the abnormal processing of full-length APP in Alzheimer's disease may occur at the NH,.terminus of the 3A4 sequence and generate a COOH-terminal fragment of 100 residues (A4CT), which includes the amyloid pA4 sequence, and the transmembrane and cytoplasmic domains of all known transmembrane APP forms.To stud~/the amyloidogenic properties of this hypo- Here we =how that expression of this APP fragment in the rabbit reticulocyte ly~ate (RRL) resulted in an aggregating protein, Membrane insertion of A4C'T obtained by expression of" gPA4CT in the presence of dog pancreas membranes prevents aggregation. Post-translational removal of the membranes led to aggregation, EXPERIMENTAL 2,1, Clonhtg pmcedurr~"Preparation of plaimid DNA, restriction enzyme digestion, al~ros¢ 8el ¢lectrophor~is of DNA, DNA libation and bacterial transform;t. tion were carried out as deicri~d by Maniatis et al, [16]. PhtsmM ¢onstrurtionConstruct SP6$/A4CT [1] was obtained by cloning the 961 bp Dell II ttindlll fra~nem of the APP595 eDNA clone [S] into pSP65, The resulting plasmid includes metllionine ¢odon 596 of AlaPfi95 as initia. tion codon, the anaylold ,BA4 Jequence (radons 597-6391640 of APP 69S) and the entire COOH.tcrminal domain, For construction of SF651SPA4CT, plasmid SP6S/A4C'rl. which was obtained by cloninga NCOI oligolinker into SphllE¢oRl.diBested SPfS/A4CT, wa~ digested with NCOI, incubated with $1 to ereat, blunt ends and ...

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“…In particular, the accumulation of aggregated amyloid β-protein in diseased brains as neurofibrillary tangles can occur through oxidation [270], and mitochondrial dysfunction has been envisaged as a radical source [271].…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Biochemistry and pathology of radical-mediated protein oxidation

Dean

Stocker

et al. 1997

Biochemical Journal

1,546

982

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Radical-mediated damage to proteins may be initiated by electron leakage, metal-ion-dependent reactions and autoxidation of lipids and sugars. The consequent protein oxidation is O2-dependent, and involves several propagating radicals, notably alkoxyl radicals. Its products include several categories of reactive species, and a range of stable products whose chemistry is currently being elucidated. Among the reactive products, protein hydroperoxides can generate further radical fluxes on reaction with transition-metal ions; protein-bound reductants (notably dopa) can reduce transition-metal ions and thereby facilitate their reaction with hydroperoxides; and aldehydes may participate in Schiff-base formation and other reactions. Cells can detoxify some of the reactive species, e.g. by reducing protein hydroperoxides to unreactive hydroxides. Oxidized proteins are often functionally inactive and their unfolding is associated with enhanced susceptibility to proteinases. Thus cells can generally remove oxidized proteins by proteolysis. However, certain oxidized proteins are poorly handled by cells, and together with possible alterations in the rate of production of oxidized proteins, this may contribute to the observed accumulation and damaging actions of oxidized proteins during aging and in pathologies such as diabetes, atherosclerosis and neurodegenerative diseases. Protein oxidation may also sometimes play controlling roles in cellular remodelling and cell growth. Proteins are also key targets in defensive cytolysis and in inflammatory self-damage. The possibility of selective protection against protein oxidation (antioxidation) is raised.

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Amyloidogenicity of rodent and human βA4 sequences

Cited by 175 publications

References 30 publications

Racemization: Its Biological Significance on Neuropathogenesis of Alzheimer's Disease.

Racemization: Its Biological Significance on Neuropathogenesis of Alzheimer's Disease.

Membrane inserted APP fragments containing the βA4 sequence of Alzheimer's disease do not aggregate

Biochemistry and pathology of radical-mediated protein oxidation

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