Inhibition of Alzheimer β-Peptide Fibril Formation by Serum Amyloid P Component

Janciauskiene, Sabina; Frutos, Pablo García de; Carlemalm, Eric; Dahlbäck, Björn; Eriksson, Sten

doi:10.1074/jbc.270.44.26041

Cited by 79 publications

(58 citation statements)

References 29 publications

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“…Like clusterin, sub-stoichiometric levels of α 2 M (at a 1:8 molar ratio of α2M:substrate) were enough to completely inhibit the formation of fibrillar Aβ aggregates (Hughes et al, 1998). Finally, it was shown that in vitro a 1:5 molar ratio of SAP to target protein completely attenuated the fibrillation of Aβ 1-42 and α 1 -antitrypsin-derived C-terminal peptides (Janciauskiene et al, 1995). There are no published data to show whether haptoglobin has similar anti-amyloidogenic properties in vitro.…”

Section: Effects Of Ecs On Amyloid Formation In Vitromentioning

confidence: 94%

“…At these low levels, clusterin was found incorporated into insoluble Aβ and SH3 fibrils . Similarly, at low SAP:Aβ ratios, SAP promoted the formation of Aβ aggregates (Hamazaki 1995); at SAP:Aβ of 1:1000, short fibrillar-like structures lacking typical amyloid features were formed which often contained associated SAP molecules (Janciauskiene et al, 1995). In addition, α 2 M has been shown to stabilize a conformation of the prion protein resistant to proteinase K (PrPRes) that is thought to initiate aggregation and is associated with prion disease pathology (Adler and Kryukov 2007).…”

Section: Effects Of Ecs On Amyloid Formation In Vitromentioning

confidence: 99%

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Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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Section: Effects Of Ecs On Amyloid Formation In Vitromentioning

confidence: 94%

Section: Effects Of Ecs On Amyloid Formation In Vitromentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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show abstract

“…90 Finally, it was shown that in vitro a 1:5 molar ratio of SAP to target protein completely attenuated the fibrillation of A and α 1 -antitrypsin-derived C-terminal peptides. 95 There are no published data to show whether haptoglobin has similar anti-amyloidogenic properties in vitro.…”

Section: Effects Of Ecs On Amyloid Formation In Vitromentioning

confidence: 99%

“…28 Similarly, at low SAP:A ratios, SAP promoted the formation of Aβ aggregates; 99 at SAP:A of 1:1000, short fibrillar-like structures lacking typical amyloid features were formed which often contained associated SAP molecules. 95 In addition,  2 M has been shown to stabilize a conformation of the prion protein resistant to proteinase K (PrPRes) that is thought to initiate aggregation and is associated with prion disease pathology. 53 Taken together, these results suggest that when ECs are present at low levels relative to the substrate they may act to stabilize an otherwise unstable conformation and facilitate amyloid fibril formation (Fig.…”

Section: Effects Of Ecs On Amyloid Formation In Vitromentioning

confidence: 99%

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

2008

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The in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. Keywords: Extracellular chaperones, receptor-mediated endocytosis, amyloid, protein quality control, aggregate toxicity, fibril formation word statement (for Contents list) plus graphic (note -colour version of below graphic provided separately)Newly identified abundant extracellular chaperones (ECs) may protect the body against dangerously hydrophobic proteins/peptides. This review proposes that ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. SUMMARYThe in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…For these reasons, a major goal of research is now focused on identifying substances that prevent -sheet formation and the accompanying precipitation of -peptide into amyloid. Despite the numerous substances known to enhance amyloidosis, relatively few are known to inhibit it [for examples, see Eriksson et al (1995), Janciauskiene et al (1995), and Wood et al (1996)], particularly in a conformationally specific manner.…”

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confidence: 99%

Nicotine Inhibits Amyloid Formation by the β-Peptide

et al. 1996

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The 42-residue -(1-42) peptide is the major protein component of amyloid plaque cores in Alzheimer's disease. In aqueous solution at physiological pH, the synthetic -(1-42) peptide readily aggregates and precipitates as oligomeric -sheet structures, a process that occurs during amyloid formation in Alzheimer's disease. Using circular dichroism (CD) and ultraviolet spectroscopic techniques, we show that nicotine, a major component in cigarette smoke, inhibits amyloid formation by the -(1-42) peptide. The related compound cotinine, the major metabolite of nicotine in humans, also slows down amyloid formation, but to a lesser extent than nicotine. In contrast, control substances pyridine and Nmethylpyrrolidine accelerate the aggregation process. Nuclear magnetic resonance (NMR) studies demonstrate that nicotine binds to the 1-28 peptide region when folded in an R-helical conformation. On the basis of chemical shift data, the binding primarily involves the N-CH 3 and 5′CH 2 pyrrolidine moieties of nicotine and the histidine residues of the peptide. The binding is in fast exchange, as shown by single averaged NMR peaks and the lack of nuclear Overhauser enhancement data between nicotine and the peptide in two-dimensional NOESY spectra. A mechanism is proposed, whereby nicotine retards amyloidosis by preventing an R-helix f -sheet conformational transformation that is important in the pathogenesis of Alzheimer's disease.

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Inhibition of Alzheimer β-Peptide Fibril Formation by Serum Amyloid P Component

Cited by 79 publications

References 29 publications

Extracellular Chaperones and Amyloids

Extracellular Chaperones and Amyloids

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

Nicotine Inhibits Amyloid Formation by the β-Peptide

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