Amyloids are insoluble fibrous protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis

Amyloidosis

In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...

, and may play a role in various neurodegenerative diseases.

Definition

The name amyloid comes from the early mistaken identification of the substance as starch

Starch

Starch or amylum is a carbohydrate consisting of a large number of glucose units joined together by glycosidic bonds. This polysaccharide is produced by all green plants as an energy store...

 (amylum in Latin

Latin

Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...

), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits were fatty

Lipid

Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...

 deposits or carbohydrate

Carbohydrate

A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...

 deposits until it was finally found that they were, in fact, deposits of proteinaceous material.

• The classical, histopathological
  Histopathology
  Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
  
   definition of amyloid is an extracellular, proteinaceous deposit exhibiting beta sheet
  Beta sheet
  The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
  
   structure. Common to most cross-beta type structures they are generally identified by apple-green birefringence
  Birefringence
  Birefringence, or double refraction, is the decomposition of a ray of light into two rays when it passes through certain anisotropic materials, such as crystals of calcite or boron nitride. The effect was first described by the Danish scientist Rasmus Bartholin in 1669, who saw it in calcite...
  
   when stained with congo red
  Congo red
  Congo red is the sodium salt of 3,3'-bis. It is a secondary diazo dye...
  
   and seen under polarized light. These deposits often recruit various sugars and other components such as Serum Amyloid P component
  Serum Amyloid P component
  Amyloid P component, serum is the identical serum form of amyloid P component , a 25kDa pentameric protein first identified as the pentagonal constituent of in vivo pathological deposits called "amyloid"...
  
  , resulting in complex, and sometimes inhomogeneous structures. 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 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, leading to some conflict in the biological community over an issue of language
  Linguistic prescription
  In linguistics, prescription denotes normative practices on such aspects of language use as spelling, grammar, pronunciation, and syntax. It includes judgments on what usages are socially proper and politically correct...
  
  .

The remainder of this article will use the biophysical context.

Diseases featuring amyloids

Disease	Protein featured	Official abbreviation
Alzheimer's disease Alzheimer's disease Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...	Beta amyloid	Aβ
Diabetes mellitus type 2 Diabetes mellitus type 2 Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...	IAPP (Amylin) Amylin Amylin, or Islet Amyloid Polypeptide , is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin .-Clinical significance:...	AIAPP
Parkinson's disease Parkinson's disease Parkinson's disease is a degenerative disorder of the central nervous system...	Alpha-synuclein Alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...	none
Transmissible spongiform encephalopathy Transmissible spongiform encephalopathy Transmissible spongiform encephalopathies , also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an...  e.g. Bovine spongiform encephalopathy Bovine spongiform encephalopathy Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...	PrPSc Prion A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...	APrP
Huntington's Disease Huntington's disease Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...	Huntingtin Huntingtin The Huntingtin gene, also called HTT or HD gene, is the IT15 gene which codes for a protein called the huntingtin protein...	none
Medullary carcinoma of the thyroid Medullary thyroid cancer Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells , which produce the hormone calcitonin....	Calcitonin Calcitonin Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...	ACal
Cardiac arrhythmias, Isolated atrial amyloidosis Isolated atrial amyloidosis Isolated atrial amyloidosis is a form of amyloidosis affecting the atria of the heart.It is associated with accumulation of atrial natriuretic factor.It may cause arrythmias....	Atrial natriuretic factor	AANF
Atherosclerosis Atherosclerosis Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...	Apolipoprotein AI	AApoA1
Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...	Serum amyloid A Serum amyloid A Serum amyloid A proteins are a family of apolipoproteins associated with high-density lipoprotein in plasma. Different isoforms of SAA are expressed constitutively at different levels or in response to inflammatory stimuli . These proteins are produced predominantly by the liver...	AA
Aortic medial amyloid	Medin	AMed
Prolactinoma Prolactinoma A prolactinoma is a benign tumor of the pituitary gland that produces a hormone called prolactin. It is the most common type of pituitary tumor... s	Prolactin Prolactin Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...	APro
Familial amyloid polyneuropathy Familial amyloid polyneuropathy Familial amyloid polyneuropathy , also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of paramyloidosis, and was first identified and described by Portuguese neurologist...	Transthyretin Transthyretin Transthyretin is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine and retinol binding protein bound to retinol. This is how transthyretin gained its name, transports thyroxine and retinol...	ATTR
Hereditary non-neuropathic systemic amyloidosis	Lysozyme Lysozyme Lysozyme, also known as muramidase or N-acetylmuramide glycanhydrolase, are glycoside hydrolases, enzymes that damage bacterial cell walls by catalyzing hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in a peptidoglycan and between...	ALys
Dialysis related amyloidosis	Beta 2 microglobulin	Aβ2M
Finnish amyloidosis	Gelsolin Gelsolin Gelsolin is an actin-binding protein that is a key regulator of actin filament assembly and disassembly. Gelsolin is one of the most potent members of the actin-severing gelsolin/villin superfamily, as it severs with nearly 100% efficiency...	AGel
Lattice corneal dystrophy Lattice corneal dystrophy type I Lattice corneal dystrophy type I is a rare form of human corneal dystrophy. It is caused by mutations in TGFBI gene encoding keratoepithelin. It has no systemic manifestations, unlike the other type of the dystrophy, LCDII. Filamentous opacities appear in the cornea with intertwining delicate...	Keratoepithelin TGFBI Transforming growth factor, beta-induced, 68kDa, also known as TGFBI , is a protein which in humans is encoded by the TGFBI gene.- Function :...	AKer
Cerebral amyloid angiopathy	Beta amyloid	Aβ
Cerebral amyloid angiopathy (Icelandic type)	Cystatin Cystatin The cystatins are a family of cysteine protease inhibitors with homology to chicken cystatin. Cystatins typically comprise about 115 amino acids, are largely acidic, contain four conserved cysteine residues known to form two disulfide bonds, may be glycosylated and/or phosphorylated, with...	ACys
systemic AL amyloidosis	Immunoglobulin light chain Immunoglobulin light chain ]The immunoglobulin light chain is the small polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains.-In humans:...  AL	AL
Sporadic Inclusion Body Myositis Inclusion body myositis Inclusion body myositis is an inflammatory muscle disease, characterized by slowly progressive weakness and wasting of both distal and proximal muscles, most apparent in the muscles of the arms and legs...	S-IBM	none

The International Society of Amyloidosis classifies amyloid fibrils based upon associated proteins.

Non-disease and functional amyloids

• Native amyloids in organisms
  • Curli E. coli Protein (curlin)
  • Chaplins from Streptomyces coelicolor
    Streptomyces coelicolor
    Streptomyces coelicolor is a soil-dwelling Gram-positive bacterium that belongs to the genus Streptomyces.-Usage in biotechnology:Strains of S. coelicolor produce various antibiotics, including actinorhodin, methylenomycin, undecylprodigiosin, and perimycin. Certain strains of S. coelicolor can...
    
    
  • Podospora Anserina Prion Het-s
  • Malaria
    Malaria
    Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
    
    l coat protein
  • Spider silk
    Spider silk
    Spider silk is a protein fiber spun by spiders. Spiders use their silk to make webs or other structures, which function as nets to catch other animals, or as nests or cocoons for protection for their offspring...
    
     (some but not all spiders)
  • Mammalian melanosome
    Melanosome
    In a biological cell, a melanosome is an organelle containing melanin, the most common light-absorbing pigment found in the animal kingdom.Cells that synthesize melanins are called melanocytes, and also the retinal pigment epithelium cells, whereas cells that have merely engulfed the melanosomes...
    
    s (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, e.g. [PSI+] (Sup35p
  Sup35p
  Sup35p is the Saccharomyces cerevisiae eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 , which forms the translation termination complex with eRF1 . This complex recognizes and catalyzes the release of the nascent polypeptide chain when the...
  
  ); [URE3] (Ure2p); [PIN+] (Rnq1p); [SWI1+] (Swi1p) and [OCT8+] (Cyc8p)

Amyloid biophysics

Amyloid is characterized by a cross-beta sheet

Beta sheet

The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...

 quaternary structure

Quaternary structure

In biochemistry, quaternary structure is the arrangement of multiple folded protein or coiling protein molecules in a multi-subunit complex.-Description and examples:...

. While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism

Circular dichroism

Circular dichroism refers to the differential absorption of left and right circularly polarized light. This phenomenon was discovered by Jean-Baptiste Biot, Augustin Fresnel, and Aimé Cotton in the first half of the 19th century. It is exhibited in the absorption bands of optically active chiral...

, or FTIR

Fourier transform infrared spectroscopy

Fourier transform infrared spectroscopy is a technique which is used to obtain an infrared spectrum of absorption, emission, photoconductivity or Raman scattering of a solid, liquid or gas. An FTIR spectrometer simultaneously collects spectral data in a wide spectral range...

 (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

X-ray

X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...

 diffraction beam. The term "cross-beta" was based on the observation of two sets of diffraction lines, one longitudinal and one transverse, that form a characteristic "cross" pattern. There are two characteristic scattering diffraction signals produced at 4.7 and 10 Ångstrom

Ångström

The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....

s (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets. 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.

Recent x-ray diffraction studies of microcrystals revealed atomistic details of core region of amyloid. In the crystallographic structure
short stretches from amyloid prone region of amyloidogenic proteins run perpendicular to the filament axis, confirming the "cross-beta" model. In addition
two layers of beta-sheet interdigite to create compact dehydrated interface termed as steric-zipper interface. There are eight classes of steric-zipper
interfaces, depending on types of beta-sheet (parallel and anti-parallel) and symmetry between two adjacent beta-sheets.

Amyloid polymer

Polymer

A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...

ization (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 or non-coded alpha-aminoisobutyric acid. For example, humans produce amylin

Amylin

Amylin, or Islet Amyloid Polypeptide , is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin .-Clinical significance:...

, an amyloidogenic peptide associated with type II diabetes, but in rats and mice prolines are substituted in critical locations 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 Trinucleotide repeat disorders

Trinucleotide repeat disorders

Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene...

 including 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

Huntington's disease

Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...

 (the longer the polyglutamine sequence

Polyglutamine tract

A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units....

, the sooner the symptoms appear), and has been confirmed in a C. elegans

Caenorhabditis elegans

Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...

model system with engineered polyglutamine peptides.

Other polypeptides and proteins such as amylin

Amylin

Amylin, or Islet Amyloid Polypeptide , is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin .-Clinical significance:...

 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 observed in vitro and possibly in vivo. This phenomenon is important since it would explain interspecies prion

Prion

A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...

 propagation and differential rates of prion propagation, as well as a statistical link between Alzheimer's and type 2 diabetes. 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. Polypeptides will not cross-polymerize their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events.

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.
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

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

.

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

Fluorescence

Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation of a different wavelength. It is a form of luminescence. In most cases, emitted light has a longer wavelength, and therefore lower energy, than the absorbed radiation...

 intensity of planar aromatic dye

Dye

A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....

s such as thioflavin T or congo red

Congo red

Congo red is the sodium salt of 3,3'-bis. It is a secondary diazo dye...

. Congo red positivity remains the gold standard for diagnosis of amyloidosis

Amyloidosis

In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...

. This is generally attributed to the environmental change, as these dyes intercalate

Intercalation (chemistry)

In chemistry, intercalation is the reversible inclusion of a molecule between two other molecules . Examples include DNA intercalation and graphite intercalation compounds.- DNA intercalation :...

 between beta-strands. Congophilic amyloid plaques generally cause apple-green birefringence

Birefringence

Birefringence, or double refraction, is the decomposition of a ray of light into two rays when it passes through certain anisotropic materials, such as crystals of calcite or boron nitride. The effect was first described by the Danish scientist Rasmus Bartholin in 1669, who saw it in calcite...

 when viewed through crossed polarimetric filters. To avoid nonspecific staining, other histology

Histology

Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...

 stains, such as the hematoxylin and eosin

H&E stain

H&E stain, HE stain or hematoxylin and eosin stain is a popular staining method in histology. It is the most widely used stain in medical diagnosis; for example when a pathologist looks at a biopsy of a suspected cancer, the histological section is likely to be stained with H&E and termed H&E...

 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

Immunohistochemistry

Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...

 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

• Bacterial Inclusion Bodies Contain Amyloid-Like Structure at SciVee
  SciVee
  SciVee is a science video sharing website where researchers can upload, view and share science video clips and connect them to scientific literature, posters and slides...
  
  
• Amyloid Cascade Hypothesis
• Stanford University Amyloid Center
• Amyloid Treatment and Research Program at Boston University
  Boston University
  Boston University is a private research university located in Boston, Massachusetts. With more than 4,000 faculty members and more than 31,000 students, Boston University is one of the largest private universities in the United States and one of Boston's largest employers...
  
  
• Amyloid: Journal of Protein Folding Disorders web page at InformaWorld
• Information, support and advice to anyone with Amyloidosis, particularly in Australia (www.amyloidosisaustralia.org)
• Amyloidosis Support Network at amyloidosis.org
• UK National Amyloidosis Centre - one of the largest amyloid diagnosis and research centres at ucl.ac.uk
• Engineering Amyloid for material at University of California, Berkeley
  University of California, Berkeley
  The University of California, Berkeley , is a teaching and research university established in 1868 and located in Berkeley, California, USA...
  
  
• Amyloidosis Foundation amyloidosisresearchfoundation.org
• National Kidney and Urologic Diseases Information Clearinghouse at National Institute of Health
• Role of anesthetics in Alzheimer's disease: Molecular details revealed
• Mini Review Amyloidosis Covering structure, mechanisms of action and kinetics of amyloid fibrils.
• Video of amyloid formation.