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Micrograph showing amyloid deposits (pink) in small bowel. H&E stain.

Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various other neurodegenerative diseases.



The name amyloid comes from the early mistaken identification of the substance as starch (amylum in Latin), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits were fatty deposits or carbohydrate deposits until it was finally resolved that it was neither, but rather a deposition of proteinaceous mass.[1]

Micrograph showing amyloid deposition in small bowel. Congo red stain.
  • The classical, histopathological definition of amyloid is an extracellular, proteinaceous deposit exhibiting beta sheet structure. Common to most cross-beta type structures they are generally identified by apple-green birefringence when stained with congo red and seen under polarized light. These deposits often recruit various sugars and other components such as Serum Amyloid P component, resulting in complex, and sometimes inhomogeneous structures.[2] Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.[3]
  • A more recent, biophysical definition is broader, including any polypeptide which polymerizes to form a cross-beta structure, in vivo, or in vitro. Some of these, although demonstrably cross-beta sheet, do not show some classic histopathological characteristics such as the Congo red birefringence. Microbiologists and biophysicists have largely adopted this definition,[4][5] leading to some conflict in the biological community over an issue of language.

The remainder of this article will use the biophysical context.

Diseases featuring amyloids

Disease Protein Featured
Alzheimer's disease Beta amyloid[6][7][8]
Type 2 diabetes mellitus IAPP (Amylin)[9][10]
Parkinson's disease Alpha-synuclein[7]
Transmissible spongiform encephalopathy e.g. Bovine Spongiform Encephalopathy aka "Mad Cow Disease" Prion[11]
Huntington's Disease Huntingtin[12][13]
Medullary carcinoma of the thyroid Calcitonin[14]
Cardiac arrhythmias Atrial natriuretic factor
Atherosclerosis Apolipoprotein AI
Rheumatoid arthritis Serum amyloid A
Aortic medial amyloid Medin
Prolactinomas Prolactin
Familial amyloid polyneuropathy Transthyretin
Hereditary non-neuropathic systemic amyloidosis Lysozyme
Dialysis related amyloidosis Beta 2 microglobulin
Finnish amyloidosis Gelsolin
Lattice corneal dystrophy Keratoepithelin
Cerebral amyloid angiopathy Beta amyloid[15]
Cerebral amyloid angiopathy (Icelandic type) Cystatin
systemic AL amyloidosis Immunoglobulin light chain AL[16]
Yeast Prions [Sup35],[17] Rnq1 (parastitic type infection in yeast). There is, in fact, no pathology associated with any yeast prion. The notion of pathology arises because the effect of one of the prion-bearing conditions mentioned ([PSI+]) is a demonstrable defect in the mechanism of protein synthesis. This has no perceptible effect on the vigour or viability of the yeast cells and can only be detected through the presence of particular gene mutations. See below under "Non-disease functional amyloids"
Sporadic Inclusion Body Myositis S-IBM
Multiple myeloma

Non-disease and functional amyloids

  • Native amyloids in organisms[18]
    • Curli E. coli Protein (curlin)
    • Chaplins from Streptomyces coelicolor
    • Podospora Anserina Prion Het-s
    • Malarial coat protein
    • Spider silk (some but not all spiders)
    • Mammalian melanosomes (pMel)
    • Tissue-type plasminogen activator (tPA), a hemodynamic factor
  • Proteins and peptides engineered to make amyloid
  • Several yeast prions are based on an infectious amyloid, eg. [PSI+] (Sup35p); [URE3] (Ure2p); [PIN+] (Rnq1p); [SWI1+] (Swi1p) and [OCT8+] (Cyc8p)

Amyloid biophysics

Amyloid is characterized by a cross-beta sheet quaternary structure; that is, the beta-strands of the stacked beta-sheets come from different protein monomers and align perpendicular to the axis of the fibril. While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the "gold-standard" test to see if a structure contains cross-beta fibres is by placing a sample in an X-ray diffraction beam. There are two characteristic scattering diffraction signals produced at 4.7 and 10 Ångstroms (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets.[citation needed] It should be noted that the "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned strands.

Amyloid polymerization (aggregation or non-covalent polymerization) is generally sequence-sensitive, that is, causing mutations in the sequence can prevent self-assembly, especially if the mutation is a beta-sheet breaker, such as proline. For example, humans produce amylin, an amyloidogenic peptide associated with type II diabetes, but in rats and mice prolines are substituted in critical locations and amyloidogenesis does not occur.[citation needed]

There are two broad classes of amyloid-forming polypeptide sequences. Glutamine-rich polypeptides are important in the amyloidogenesis of Yeast and mammalian prions, as well as Huntington's disease. When peptides are in a beta-sheet conformation, particularly when the residues are parallel and in-register (causing alignment), glutamines can brace the structure by forming intrastrand hydrogen bonding between its amide carbonyls and nitrogens. In general, for this class of diseases, toxicity correlates with glutamine content.[citation needed] This has been observed in studies of onset age for Huntington's disease (the longer the polyglutamine sequence, the sooner the symptoms appear), and has been confirmed in a C. elegans model system with engineered polyglutamine peptides.[citation needed]

Other polypeptides and proteins such as amylin and the Alzheimer's beta protein do not have a simple consensus sequence and are thought to operate by hydrophobic association.[citation needed] Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity.[citation needed]

For these peptides, cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is observed in vitro and possibly in vivo.[citation needed] This phenomenon is important since it would explain interspecies prion propagation and differential rates of prion propagation, as well as a statistical link between Alzheimer's and type 2 diabetes.[citation needed] In general, the more similar the peptide sequence the more efficient cross-polymerization is, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" which prevent polymerization.[citation needed] Polypeptides will not cross-polymerize their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events.[citation needed]

Amyloid pathology

The reasons for amyloid association with disease is unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death.[19] [8]

Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species (ROS), which can initiate a signaling pathway leading to apoptosis [20].

These proteins are typically characterized by their ability to cause aggregation of healthy protein.

Histological staining

Clinically, amyloid diseases are typically identified by a change in the fluorescence intensity of planar aromatic dyes such as thioflavin T or congo red. Congo red positivity remains the gold standard for diagnosis of amyloidosis. This is generally attributed to the environmental change, as these dyes intercalate between beta-strands. Congophilic amyloid plaques generally cause apple-green birefringence when viewed through crossed polarimetric filters. To avoid nonspecific staining, other histology stains, such as the hematoxylin and eosin stain, are used to quench the dyes' activity in other places such as the nucleus where the dye might bind. Modern antibody technology and immunohistochemistry has made specific staining easier, but often this can cause trouble because epitopes can be concealed in the amyloid fold; an amyloid protein structure is generally a different conformation from that which the antibody recognizes.


  1. ^ Kyle, R.A. (2001) Amyloidosis: a convoluted story. Brit. J. Haem. 114:529-538. PMID 11552976
  2. ^ Sipe, J. D. and Cohen, A.S. (2000) Review: History of the Amyloid Fibril. J. Struct. Biol. 130:88-98. PMID 10940217
  3. ^ Lin CY, Gurlo T, Kayed R, et al. (May 2007). "Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced beta-cell apoptosis in h-IAPP transgenic mice". Diabetes 56 (5): 1324–32. doi:10.2337/db06-1579. PMID 17353506. 
  4. ^ Nilsson MR (September 2004). "Techniques to study amyloid fibril formation in vitro". Methods (San Diego, Calif.) 34 (1): 151–60. doi:10.1016/j.ymeth.2004.03.012. PMID 15283924. 
  5. ^ Fändrich M (August 2007). "On the structural definition of amyloid fibrils and other polypeptide aggregates". Cellular and molecular life sciences : CMLS 64 (16): 2066–78. doi:10.1007/s00018-007-7110-2. PMID 17530168. 
  6. ^ Chiang PK, Lam MA, Luo Y (September 2008). "The many faces of amyloid beta in Alzheimer's disease". Current molecular medicine 8 (6): 580–4. doi:10.2174/156652408785747951. PMID 18781964. 
  7. ^ a b Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM (2008). "Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases". Molecular medicine (Cambridge, Mass.) 14 (7-8): 451–64. doi:10.2119/2007-00100.Irvine. PMID 18368143. 
  8. ^ a b Ferreira ST, Vieira MN, De Felice FG (2007). "Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases". IUBMB life 59 (4-5): 332–45. doi:10.1080/15216540701283882. PMID 17505973. 
  9. ^ Haataja L, Gurlo T, Huang CJ, Butler PC (May 2008). "Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis". Endocrine reviews 29 (3): 303–16. doi:10.1210/er.2007-0037. PMID 18314421. 
  10. ^ Höppener JW, Ahrén B, Lips CJ (August 2000). "Islet amyloid and type 2 diabetes mellitus". The New England journal of medicine 343 (6): 411–9. doi:10.1056/NEJM200008103430607. PMID 10933741. 
  11. ^ "More than just mad cow desease", Nature Structural Biology 8, 281 (2001) doi:10.1038/86132
  12. ^ Truant R, Atwal RS, Desmond C, Munsie L, Tran T (September 2008). "Huntington's disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases". The FEBS journal 275 (17): 4252–62. doi:10.1111/j.1742-4658.2008.06561.x. PMID 18637947. 
  13. ^ Weydt P, La Spada AR (August 2006). "Targeting protein aggregation in neurodegeneration--lessons from polyglutamine disorders". Expert opinion on therapeutic targets 10 (4): 505–13. doi:10.1517/14728222.10.4.505. PMID 16848688. 
  14. ^ "Amyloidosis, Overview" by Bruce A Baethge and Daniel R Jacobson
  15. ^ Dotti CG, De Strooper B (February 2009). "Alzheimer's dementia by circulation disorders: when trees hide the forest". Nat. Cell Biol. 11 (2): 114–6. doi:10.1038/ncb0209-114. PMID 19188916. 
  16. ^ "Amyloidosis, Overview" by Bruce A Baethge and Daniel R Jacobson
  17. ^ Nakayashiki T, Kurtzman CP, Edskes HK, Wickner RB (July 2005). "Yeast prions [URE3 and [PSI+] are diseases"]. Proceedings of the National Academy of Sciences of the United States of America 102 (30): 10575–80. doi:10.1073/pnas.0504882102. PMID 16024723. 
  18. ^ Hammer ND, Wang X, McGuffie BA, Chapman MR (May 2008). "Amyloids: friend or foe?". Journal of Alzheimer's disease : JAD 13 (4): 407–19. PMID 18487849. PMC 2674399. 
  19. ^ Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG (April 2005). "Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers". The Journal of biological chemistry 280 (17): 17294–300. doi:10.1074/jbc.M500997200. PMID 15722360. >
  20. ^ Kadowaki H. et al. (2005). "Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation". Cell Death Differ 12 (1): 19–24. doi:10.1038/sj.cdd.4401528. PMID 15592360. 

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