Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie?

Jarrett, Joseph T.; Lansbury, Peter T.

doi:10.1016/0092-8674(93)90635-4

Cited by 2,062 publications

(1,608 citation statements)

References 23 publications

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“…1A-D, the fluorescence of ThT followed a characteristic sigmoidal curve when fresh Aß(1-40) or Aß(1-42) was incubated at 37˚C. This curve is consistent with a nucleation-dependent polymerization model (Jarrett and Lansbury, 1993;Naiki and Gejyo, 1999).…”

Section: Effect Of Nsaids On the Kinetics Of Faß Polymerizationsupporting

confidence: 69%

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

et al. 2005

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The pathogenesis of Alzheimer's disease (AD) is characterized by cerebral deposits of amyloid ß-peptides (Aß) and neurofibrillary tangles which are surrounded by inflammatory cells. Long-term uses of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of developing AD and delay the onset of the disease. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of NSAIDs such as ibuprofen, aspirin, meclofenamic acid sodium salt, diclofenac sodium salt, ketoprofen, flurbiprofen, naproxen, sulindac sulfide and indomethacin on the formation, extension, and destabilization of ß-amyloid fibrils (fAß) at pH 7.5 at 37˚C in vitro. All examined NSAIDs dose-dependently inhibited formation of fAß from fresh Aß(1-40) and Aß(1-42), as well as their extension. Moreover, these NSAIDs dose-dependently destabilized preformed fAßs. The overall activity of the molecules examined was in the following order: ibuprofen ≈ sulindac sulfide ≥ meclofenamic acid sodium salt > aspirin ≈ ketoprofen ≥ flurbiprofen ≈ diclofenac sodium salt > naproxen ≈ indomethacin. Although the mechanisms by which these NSAIDs inhibit fAß formation from Aß, and destabilize preformed fAß in vitro are still unclear, NSAIDs may be promising for the prevention and treatment of AD.

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Section: Effect Of Nsaids On the Kinetics Of Faß Polymerizationsupporting

confidence: 69%

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

et al. 2005

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“…It appears that the aggregation behaviours of various amyloid-forming peptides and proteins are strikingly similar. The kinetics of amyloid formation (as measured by Thioflavin T fluorescence or light scattering) is generally characterized by an initial 'lag' or nucleation phase, followed by a rapid exponential 'growth' or polymerization phase, 4 and lastly, by a plateau phase in which no further polymerization occurs (Fig. 1).…”

Section: Amyloid Formationmentioning

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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“…This approach for labeling amyloid lesions takes advantage of the high affinity binding A␤ peptides have to other A␤ peptides (Jarrett and Lansbury, 1993;Wadghiri et al, 2003). However, A␤ peptides are toxic and deposited A␤ can seed further amyloid deposition (Jarrett and Lansbury, 1993;Yankner et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

“…In this initial study we used Gd-DTPA-A␤1-40. However, the use of full-length A␤ for this purpose may have toxic side effects and can actually promote plaque buildup, since A␤ is known to seed amyloid deposition (Jarrett and Lansbury, 1993). Hence, we developed a compound, Gd-DTPA-K6A␤1-30, that does not form amyloid aggregates and is non-toxic while maintaining high affinity for A␤.…”

Section: Introductionmentioning

confidence: 99%

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice

Sigurdsson

Wadghiri

Mosconi

et al. 2008

Neurobiology of Aging

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Amyloid plaques are a characteristic feature in Alzheimer's disease (AD). A novel non-toxic contrast agent is presented, Gd-DTPA-K6A␤1-30, which is homologous to A␤, and allows plaque detection in vivo. MRI was performed on AD model mice and controls prior to and following intracarotid injection with Gd-DTPA-K6A␤1-30 in mannitol solution, to transiently open the blood-brain barrier. A gradient echo T2 * -weighted sequence was used to provide 100 m isotropic resolution with imaging times of 115 min. The scans were examined with voxel-based analysis (VBA) using statistical parametric mapping, for un-biased quantitative comparison of ligand-injected mice and controls. The results indicate that: (1) Gd-DTPA-K6A␤1-30 is an effective, non-toxic, ligand for plaque detection when combined with VBA (p ≤ 0.01-0.001), comparing pre and post-ligand injection scans. (2) Large plaques can be detected without the use of a contrast agent and this detection co-localizes with iron deposition. (3) Smaller, earlier plaques require contrast ligand for MRI visualization. Our ligand when combined with VBA may be useful for following therapeutic approaches targeting amyloid in transgenic mouse models.

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Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie?

Cited by 2,062 publications

References 23 publications

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

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

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice

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