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.

Definition controversy

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. [Kyle, R.A. (2001) Amyloidosis: a convoluted story. "Brit. J. Haem." 114:529-538. PMID 11552976]

* The classical, histopathological definition of amyloid is an extracellular, proteinaceous deposit exhibiting beta sheet structure. This is due to mis-folding of unstable proteins. 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. [Sipe, J. D. and Cohen, A.S. (2000) Review: History of the Amyloid Fibril. "J. Struct. Biol." 130:88-98. PMID 10940217] Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.

* A more recent, "biophysical" definition is broader, including any polypeptide which adopts a cross-beta polymerization, "in vivo", or "in vitro". Some of these, although demonstrably cross-beta sheet, fail other characteristic tests of amyloid, such as the Congo red birefringence test. Microbiologists and biophysicists have largely adopted this definition, leading to some conflict in the biological community over an issue of language.

The remainder of this article will be "inclusive" with due deference to the controversy by indicating where amyloid species are observed only in the biophysical context.

Diseases featuring amyloids

*Alzheimer's disease (Beta amyloid)
*Type 2 diabetes mellitus (IAPP)
*Parkinson's disease (Alpha-synuclein)
*Transmissible spongiform encephalopathy aka "Mad Cow Disease" (Prion)
*Medullary carcinoma of the thyroid
*Yeast Prions [Sup35] ,Nakayashiki, PNAS, 2005] Rnq1
*Sporadic Inclusion Body Myositis (S-IBM)
*Medullary carcinoma of the thyroid (Calcitonin)

Non-disease amyloids

(mostly using the biophysical definition)

* Native amyloids in organisms
** 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

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. 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 an amyloidogenic peptide associated with type II diabetes, but, in Rodentia, a proline is substituted in a critical location and amyloidogenesis does not occur.

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. 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.

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. Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity.

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

Xu, using atomic force microscopy, has shown in both lysozyme and human tau40 that formation of amyloid fibers is a two-step process in which proteins first aggregate into uniform colloidal spheres of ~20nm diameter.Xu S. Aggregation drives "misfolding" in protein amyloid fiber formation. "Amyloid" 2007 Jun;14(2):119-31. PMID 17577685] The spheres then join to form characteristic linear chains, which evolve over time into mature amyloid fibers. He proposes that colloidal aggregation drives conformational change and that a conformational change is not essential to initiate the aggregation process.

Amyloid pathology

The reasons for amyloid association with disease is unclear. In many cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. In other cases, amyloid deposition precedes cell death, suggesting small amyloid-like oligomers (possibly but not necessarily biophysically amyloid) cause cell death. There is significant speculation that amyloid fibrils can also puncture cells or cause problems such as ionic imbalance in cells. Further speculation has led to the hypothesis that while amyloid association may be the cause of health issues, the association itself is initiated by an underlying problem, such as one/some of the above mentioned side effects like calcium ion concentration imbalances.

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 [ Kadowaki et al., 2005. Amyloid bold italic beta induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death and Differentiation 12:19-24. [] ] .

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, histology stains, such as hematoxylin and eosin stain, are used to quench the dyes' activity in other places where the dye might bind, such as the nucleus. 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.


External links

* [ Amyloid Peptides] at
* [ Amyloid Precursor Protein, CTF fragments] at
* [ Amyloid Treatment and Research Program] at Boston University
* [ Amyloid: Journal of Protein Folding Disorders web page] at
* [ Amyloidosis web page] at Cornell University
* [ Information, support and advice to anyone with Amyloidosis, particularly in Australia] (
* [ Amyloidosis Support Network] at
* [ UK National Amyloidosis Centre - one of the largest amyloid diagnosis and research centres] at
* [ Engineering Amyloid for material] at University of California, Berkeley
* [ Amyloidosis Foundation]
* [ National Kidney and Urologic Diseases Information Clearinghouse] at National Institute of Health
* [ Amyloid Cascade Hypothesis]

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