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Micrograph showing amyloid deposits (pink) in small bowel. Duodenum with amyloid deposition in lamina propria. Amyloid shows up as homogeneous pink material in lamina propria and around blood vessels. 20X

Amyloids are aggregates of proteins that become folded into a shape that allows many copies of that protein to stick together, forming fibrils. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal physiological functions and form fibrous deposits in plaques around cells which can disrupt the healthy function of tissues and organs.

Such amyloids have been associated with (but not necessarily as the cause of) more than 50[1] human diseases, known as amyloidosis, and may play a role in some neurodegenerative disorders.[2] Some amyloid proteins are infectious; these are called prions in which the infectious form can act as a template to convert other non-infectious proteins into infectious form.[3] Amyloids may also have normal biological functions; for example, in the formation of fimbriae in some genera of bacteria, transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans.[4]

Amyloids have been known to arise from many different proteins.[5] These polypeptide chains generally form β-sheet structures that aggregate into long fibers; however, identical polypeptides can fold into multiple distinct amyloid conformations. The diversity of the conformations may have led to different forms of the prion diseases.[4]

Amyloid of HET-s(218-289) prion pentamer, Podospora anserina (PDB: 2rnm​).


The name amyloid comes from the early mistaken identification by Rudolf Virchow of the substance as starch (amylum in Latin, from Greek ἄμυλον amylon), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits are fatty deposits or carbohydrate deposits until it was finally found (in 1859) that they are, in fact, deposits of albumoid proteinaceous material.[6]

  • The classical, histopathological definition of amyloid is an extracellular, proteinaceous deposit exhibiting beta sheet structure. Common to most cross-beta-type structures, in general, they are 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.[7] Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.[8]
  • A more recent, biophysical definition is broader, including any polypeptide that 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.[citation needed] Microbiologists and biophysicists have largely adopted this definition,[9][10] 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 amyloidsEdit

Non-disease and functional amyloidsEdit

  • Native amyloids in organisms[24]
    • Curli fibrils produced by E. coli, Salmonella, and a few other members of the Enterobacteriales (Csg). The genetic elements (operons) encoding the curli system are phylogenetic widespread and can be found in at least four bacterial phyla.[25] This suggest that many more bacteria may express curli fibrils.
    • Gas vesicles, the buoyancy organelles of aquatic archaea and eubacteria[26]
    • Functional amyloids in Pseudomonas (Fap)[27][28]
    • 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
    • ApCPEB protein and its homologues with a glutamine-rich domain
    • Fungal cell adhesion proteins aggregate on the surface of the fungi to form cell surface amyloid regions with greatly increased binding strength [29][30]
  • Peptide/protein hormones stored as amyloids within endocrine secretory granules[31]
  • Proteins and peptides engineered to make amyloid that display specific properties, such as ligands that target cell surface receptors[32]
  • Several yeast prions are based on an infectious amyloid, e.g. [PSI+] (Sup35p); [URE3] (Ure2p); [PIN+] (Rnq1p); [SWI1+] (Swi1p) and [OCT8+] (Cyc8p)
  • Functional amyloids are abundant in most environmental biofilms according to staining with amyloid specific dyes and antibodies[33]
  • The tubular sheaths encasing Methanosaeta thermophila filaments are the first functional amyloids to be reported from archeal domain of life [34]

"Amyloid deposits occur in the pancreas of patients with diabetes mellitus, although it is not known if this is functionally important. The major component of pancreatic amyloid is a 37-amino acid residue peptide known as islet amyloid polypeptide or amylin. This is stored with insulin in secretory granules in B cells and is co secreted with insulin" (Rang and Dale's Pharmacology, 2015).

ATTR amyloid deposits from transthyretin occur not only in Transthyretin-related hereditary amyloidosis, but also in advanced cases of aging in many tissues, in many mammalian species. They are a common result in supercentenarian autopsies. A proposal is that they may mediate some tissue pathologies seen in advanced aging, and pose a limit to human life span.[35]

Amyloid biophysicsEdit


Amyloids are formed of long unbranched fibers that are characterized by a cross-beta sheet quaternary structure in which antiparallel chains of β-stranded peptides are arranged in an orientation perpendicular to the axis of the fiber. Each individual fiber may be 5–15 nanometres in width and a few micrometres in length.[4] While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the "gold-standard" test to see whether a structure contains cross-β fibres is by placing a sample in an X-ray diffraction beam. The term "cross-β" was based on the observation of two sets of diffraction lines, one longitudinal and one transverse, that form a characteristic "cross" pattern.[36] 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.[37] 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. The cross-beta pattern is considered a diagnostic hallmark of amyloid structure.[4]

For a long time our knowledge of the atomic-level structure of amyloid fibrils was limited by the fact that they are unsuitable for the most traditional methods for studying protein structures. Recent years have seen progress in experimental methods that now enable direct data on the internal structure of different types of amyloid fibrils. Two prominent methods include the use of solid-state NMR spectroscopy and (cryo) electron microscopy. Combined, these methods have provided 3D atomic structures of amyloid fibrils formed by amyloid β peptides, α-synuclein, tau, and the FUS protein, associated with various neurodegenerative diseases.[38][39]

X-ray diffraction studies of microcrystals revealed atomistic details of core region of amyloid.[40][41] The crystallographic structures show that short stretches from amyloid-prone regions of amyloidogenic proteins run perpendicular to the filament axis, consistent with the "cross-β" feature of amyloid structure. They also reveal a number of characteristics of amyloid structures – neighboring β-sheets are tightly packed together via an interface devoid of water (therefore referred to as dry interface), with the opposing β-strands slightly offset from each other such that their side-chains interdigitate. This compact dehydrated interface created was termed a steric-zipper interface.[4] There are eight theoretical classes of steric-zipper interfaces, dictated by the directionality of the β-sheets (parallel and anti-parallel) and symmetry between adjacent β-sheets.

Although bona fide amyloid structures always are based on intermolecular β-sheets, different types of "higher order" tertiary folds have been observed or proposed. The β-sheets may form a β-sandwich, or a β-solenoid which may be either β-helix or β-roll. One complicating factor in studies of amyloidogenic polypeptides is that identical polypeptides can fold into multiple distinct amyloid conformations.[4] This phenomenon is typically described as amyloid polymorphism.[42][43] .[44] It has notable biological consequences given that it is thought to explain the prion strain phenomenon, for example.[citation needed]


Amyloid is formed through the polymerization of hundreds to thousands of monomeric peptides into long fibers. In general, amyloid polymerization (aggregation or non-covalent polymerization) is 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 or non-coded alpha-aminoisobutyric acid.[45] 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] Studies comparing synthetic to recombinant Amyloid beta 1-42 in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant Amyloid beta 1-42 has a faster fibrillation rate and greater toxicity than synthetic Amyloid beta 1-42 peptide.[46] This observation combined with the irreproducibility of certain Amyloid beta 1-42 experimental studies has been suggested to be responsible for the lack of progress in Alzheimer's research.[47] Consequently, there have been renewed efforts to manufacture Amyloid beta 1-42 and other amyloid peptides at unprecedented (>99%) purity.[48]

There are multiple classes of amyloid-forming polypeptide sequences.[42][43][44] Glutamine-rich polypeptides are important in the amyloidogenesis of Yeast and mammalian prions, as well as Trinucleotide repeat disorders including Huntington's disease. When glutamine-rich polypeptides are in a β-sheet conformation, glutamines can brace the structure by forming inter-strand hydrogen bonding between its amide carbonyls and nitrogens of both the backbone and side chains. The onset age for Huntington's disease shows an inverse correlation with the length of the polyglutamine sequence, with analogous findings in a C. elegans model system with engineered polyglutamine peptides.[49]

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.[50][51]

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.[52] 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" that 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]

The fast aggregation process, rapid conformational changes as well as solvent effects provide challenges in measuring monomeric and oligomeric amyloid peptide structures in solution. Theoretical and computational studies complement experiments and provide insights that are otherwise difficult to obtain using conventional experimental tools. Several groups have successfully studied the disordered structures of amyloid and reported random coil structures with specific structuring of monomeric and oligomeric amyloid as well as how genetics and oxidative stress impact the flexible structures of amyloid in solution.[53]

Oligomeric intermediates of insulin during fibrillation (more toxic than other intermediates: native, protofibril, and fibril) decreased the surface tension of solution which indicated to detergent-like properties of oligomers and significant role of hydrophobic forces in cytotoxicity of oligomers.[54]

Amyloid pathologyEdit

The reasons for amyloid association disease are 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.[13][55]

Calcium dysregulation has been observed in cells exposed to amyloid oligomers. These small aggregates can form ion channels planar lipid bilayer membranes. Channel formation has been hypothesized to account for calcium dysregulation and mitochondrial dysfunction by allowing indiscriminate leakage of ions across cell membranes.[56]

Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species (ROS), which can initiate a signalling pathway leading to apoptosis.[57]

There are reports that indicate amyloid polymers (such as those of huntingtin, associated with Huntington's disease) can induce the polymerization of essential amyloidogenic proteins, which should be deleterious to cells. Also, interaction partners of these essential proteins can also be sequestered.[58]

Histological stainingEdit

In the clinical setting, amyloid diseases are typically identified by a change in the fluorescence intensity of planar aromatic dyes such as thioflavin T, congo red or NIAD-4.[59] In general, this is attributed to the environmental change, as these dyes intercalate between beta-strands to confine their structure.[60] Congo Red positivity remains the gold standard for diagnosis of amyloidosis. In general, binding of Congo Red to amyloid plaques produces a typical apple-green birefringence when viewed under cross-polarized light. Recently, significant enhancement of fluorescence quantum yield of NIAD-4 was exploited to super-resolution fluorescence imaging of amyloid fibrils[61] and oligomers.[62] 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; in general, an amyloid protein structure is a different conformation from the one that the antibody recognizes.

See alsoEdit


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