• A little history of amyloid [Sipe and Cohen, 2000]
  • The term amyloid originated from macroscopic observations conducted on cerebral material in 1854 by Rudolph Virchow. The tissue abnormalities showed by this brain sample revealed some properties similar to those of cellulose, therefore Virchow called them amyloid, from the Latin amylum and the Greek amylon.

    Five years later, Friedreich and Kekule discovered that the supposed cellulosic nature of amyloid was actually wrong, by demonstrating the apparent absence of carbohydrates in amyloid aggregates. Instead, proteins were found in significant amount, leading to the desription of a new class of proteins, called amyloid proteins. In the following years, and during the 20th century, what was first thought to be a single group of proteins proved to contain numerous families of proteins. Those showed an important variety of functions, and were found in organisms ranging from yeast to mammals.

    Primary observations of amyloid aggregates using light microscopy and histopathologic dyes showed an amorphous structure. However, in 1927, Divry and Florkin pointed out a positive birefringence of the long axis of unstained and Congo red-stained amyloid deposit. Over the years, congophilia with apple green birefringence became the first specific trait of amyloid.

    In the late 50's, the use of electron microscopy allowed Cohen and Calkins to demonstrate the fibrillar structure of amyloid. Many experiments led after that proved this fibrillar morphology to exist in all kinds of human or animal amyloidotic tissues. The fibrillar state became then the second criterion defining amyloid.

    Over the last forty years, significant progress have been made, due to the development of isolation and purification techniques. In particular, the structure of the amyloid proteins has been highly studied, as were their potential ways of aggregation. This led, in 1968 and 1969, to the definition of the third distinctive feature of amyloid, the cross-beta shape showed by x-ray diffraction in the aggregates.

  • Amyloidosis [Selkoe, 2003; Kelly 1996; Jackson and Clarke, 2000]
  • Formation of insoluble fibers by soluble proteins undergoing conformationnal changes is very common : under in vitro denaturing conditions, most proteins will assemble themselves into aggregates in every way similar to amyloid fibrils. But this phenomenon occurs in vivo only for a small number of proteins, the amyloid ones.

    Indeed, under very specific conditions (genetic mutations, environmental factors, ...), amyloid proteins undergo structural modifications, giving birth to new stable isoforms, called amyloidogenic isoforms. The following aggregation leads to pathological symptoms, amyloid proteins beeing involved in numerous diseases, known as amyloidosis. Some of those pathologies are among the most serious neurodegenerative ones, like Alzheimer's, Huntington's, Parkinson's or the transmissible encephalopathies.

    However, some papers recently brought a new light on the consequences of amyloid formation : the amyloidogenic isoforms and the aggregates may sometimes have important biological functions. For instance, the Het-s protein found in Neurospora Crassa is well-known for its role in cytoplasmic incompatibility [Balguerie et al., 2003]. The function of some proteins found in humans might also relie on their fibrillogenic nature, like Pmel17, involved in melanin storage in melanosomes [Berson et al, 2003], or a neuronal member of the CPEB family wich regulates mRNA translation and could be involved in memory process [Si et al., 2003]. Even A-beta, involved in Alzheimer's disease, may not be as neurotoxic as it was thought to be, but instead may have a neuroprotective function [Savory et al., 2002].

  • Prions [Aguzzi and Polymenidou, 2004; Zhouravleva et al., 2002]
  • Some amyloid proteins, termed prions, show a very unusual behavior : not only do they form amyloid deposits, but they also possess the ability to spread the aggregation phenomenon to other cells, or even to other organisms.

    The prion concept was originally proposed in 1982 by Stanley Prusiner, to explain the peculiar transmission of the Creutzfeldt-Jakob disease. He showed the propagating agent was of proteinous nature, consisting of little aggregates of a modified isoform of PrP (Prion Protein), a normal component of the cell. Further work allowed him to define a prion as "a proteinaceous infectious particle that lacks nucleic acid", a definition also known as the "protein-only hypothesis".

    The PrP protein is the only mammalian prion protein known to date, but other prions have been found in yeast or in fungus, where the prion phenomenon seems to be widespread. In these unicellular organisms, prionic isoforms do not always induce pathological phenotypes : they can also work as non-genetic inheritance elements. The prion statement about infectious particles might then evolve into a wider definition, that would include the ability to propagate phenotypical variability.

  • The Amyloid Protein DataBase
  • There are currently 33 amyloid protein families stored in AmyPDB. All of those families are listed below, including the number of sequences collected for each of them.

    Name Description Listed sequences
    (Apo)-Serum amyloid A
    Functions

    Serum amyloid A is an acute phase protein. It is expressed mainly in the liver. Though its role is not well understood, it is involved in cholesterol regulation, activation of secretory cholesterol phospholipases, and mediation of monocytes, granulocytes and T-cells. It also possess inhibitory effects on inflammation.

    Pathologies

    SAA is a precursor protein in inflammation-associated reactive amyloidosis (AA-type). Among the 3 human isoforms, only SAA1 and SAA2 have been identified in amyloid aggregates.

    74
    (Pro)-Calcitonin
    Functions

    Calcitonin is a 32 residues peptide hormone, produced by the thyroid gland in humans. It lowers plasma calcium and phosphate levels without augmenting calcium accretion.

    Pathologies

    In medullary thyroid cancer (MTC), calcitonin produced by tumorous cells forms amyloid deposits.

    37
    A-beta protein precursor
    Functions

    The APP (Amyloid Precursor Protein) comprises a large extracellular N-terminal domain, a short hydrophobic membrane-spanning domain, and a short C-terminal region. The 40-residue Abeta is a proteolytic product of this protein, encompassing the end of the N-terminal region and the transmembrane domain. Aberrant catabolism of APP seems to lead to the formation of Abeta.

    Pathologies

    This peptide is implicated in the pathogenesis of Alzheimer's disease and aged Down's Syndrome (which is promoted by the acquisition of an additional copy of chromosome 21).
    In Alzheimer's disease, the brain is characterised by extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and vascular and neuronal damage. The major peptide found within these deposits is Abeta.

    125
    A-S2C casein


    0
    ABriPP/ADanPP
    Functions

    This highly insoluble peptide is a fragment of a putative type-II single-spanning transmembrane precursor.

    Pathologies

    The Familial British Dementia (FBD), also called familial cerebral amyloid angiopathy-British type, is due to a single base substitution at the stop codon of the BRI gene. This mutation generates a 27 aa protein, wich 34 carboxy-terminal amino acids form the ABri peptide found in amyloid aggregates of FBD.

    3
    Alpha Synuclein
    Functions

    It is a presynaptic protein, the function of wich is still not fully understood. It might be involved in the modulation of synaptic transmission, in the regulation of the localization of vesicles in synapses, and in neuronal plasticity.

    Pathologies

    Alpha synuclein is involved in several neurodegenerative pathologies, called synucleinopathies, such as Alzheimer's and Parkinson's diseases, or progressive autonomic failure and neurodegeneration with type 1 brain iron accumulation.
    A 35 residues fragment, called NAC, has been found in senile plaques and Lewy bodies typical of Alzheimer's and Parkinson's diseases, while two mutations (Ala35Pro and Ala 53Thr) lead to the accumulation of the entire protein in Lewy bodies.


    21
    Apolipoprotein A I
    Functions

    It plays a critical role in lipid metabolism : it is the major protein component of high density lipoprotein particles and plays a key role in the solubilization of lipids in these particles, the activation of lecithin cholesterol acyltransferase, the binding of high density lipoprotein to cell surfaces, and the promotion of cholesterol efflux from cells.

    Pathologies

    The N-terminal region of apolipoprotein A-1 has been found in amyloid fibrils of autosomal dominant systemic amyloidosis. Those amyloidosis are due to either the wild type apolipoprotein A1, or mutants of this protein, like Arg84 or Iowa variants.

    54
    Apolipoprotein A II


    0
    Apolipoprotein A IV


    0
    Atrial natriuretic factor
    Functions

    The atrial natriuretic factor plays an important role in the homeostasis of blood pressure as well as in sodium balance.

    Pathologies

    Aggregates containing the atrial natiurectic factor are characteristic of the Isolated Atrial Amyloid (IAA), a very common age-related amyloid form only seen in the atria of the heart.

    34
    Beta 2 Microglobulin
    Functions

    Beta 2 Microglobulin is the non-covalently bound light-chain of the class I human leukocyte antigen (HLA class 1).

    Pathologies

    Beeing normally degraded by kidneys, serum beta 2 microglobulin accumulates in case of renal failure, leading to the aggregation of the full length protein, mosttly in the musculoskeletal system.

    141
    Corneodesmin


    0
    Cystatin C
    Functions

    Cystatin C, as well as other cystatins, is a natural cysteine protease inhibitor.

    Pathologies

    Wild type cystatin C has been shown to accumulate within amyloid-beta (A beta) amyloid deposits in Alzheimer's disease (AD) brain. Aggregation of calcitonin is also involved in sporadic cerebral amyloid angiopathy, while a variant human cystatin C (L68Q) is responsible for autosomal dominant cerebral amyloid angiopathy.

    67
    Fibrinogen alpha
    Functions

    Fibrinogen is an acute phase protein as well as a component of the coagulation cascade. It is found in hexameres of alpha, beta and gamma chains.

    Pathologies

    Arg554Leu and Glu526Val mutations are responsible for autosomal dominant hereditary hepatic or renal amyloidosis.

    59
    Galectin


    0
    Gelsolin
    Functions

    This calcium-dependent actin-binding protein modulates actin filament length. It thus influences the structure of the cytoskeleton and plays a key role in cellular motility and differentiation.

    Pathologies

    Wild-type gelsolin is normally stabilized by Ca2+ binding. This stabilization lacks in D187N and D187Y variants, allowing access to a furin cleavage site. Furin processing liberates an amyloidogenic fragment, which aggregation leads to gelsolin familial amyloidosis.

    39
    Huntingtin
    Functions

    Huntingtin is involved in fast axonal trafficking.

    Pathologies

    Polyglutamine expansion in the N-terminal region of huntingtin plays a central role in Huntington's disease, by causing protein aggregation that leads to neurotoxicity.

    19
    Immunoglobulin heavy chain


    0
    Immunoglobulin light chain
    Functions

    Immunoglobulins are large glycoproteins that are secreted by plasma cells. They are acting as antibodies in the immune response by binding with specific antigens. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM.

    Pathologies

    Light-chain (L-chain) amyloidosis is characterized by deposition of fibrillar aggregates composed of the N-terminal L-chain variable region (VL) domain of an immunoglobulin, generally in individuals overproducing a monoclonal L chain.

    0
    Insulin
    Functions

    This hormone is secreted by the islets of Langerhans, and is involved in the regulation of the metabolism of carbohydrates and fats, especially the conversion of glucose to glycogen, which lowers the blood glucose level.

    Pathologies

    Localised amyloidosis has been shown at the sites of injections for a patient with type 1 (insulin-dependent) diabete. Insulin aggregates have also been found in insulin infusion pump.

    160
    Islet amyloid polypeptide
    Functions

    IAPP is an hormone produced by pancreatic beta cells, that moderates the glucose lowering effects of insulin.

    Pathologies

    IAPP is the peptide subunit of amyloid found in pancreatic islets of type 2 diabetic patients and in insulinomas.

    17
    Kerato-epithelin


    0
    Lactadherin
    Functions

    This glycoprotein was previously known to be expressed by mammary epithelial cells as a cell surface protein and secreted as part of the milk fat globule membrane. But recently, it was found to be expressed by aortic medial smooth muscle cells. A possible function has been shown in vitro : lactadherin might act as an anticoagulant, by competing with blood coagulation proteins for phospholipid binding sites.

    Pathologies

    The aggregation of a 50 residues fragment of lactadherin, called medin, leads to aortic medial amyloid, a form of localized amyloid very common in individuals older than 60 years. But the importance and effects of those amyloid deposits remain unknown.

    5
    Lactoferrin
    Functions

    Lactoferrin is a red iron-binding protein synthesized by neutrophils and glandular epithelial cells. It is found in many human secretions (as tears and milk), retarding bacterial and fungal growth.

    Pathologies

    Amyloid deposits containing lactoferrin have been discovered in the cornea, seminal vesicles, and brain.

    34
    Leukocyte chemotactic factor-2


    0
    Lung surfactant protein
    Functions

    This 35-residues protein is the major component of lung surfactant.

    Pathologies

    The conformation of SP-C can change from a monomeric alpha-helix to beta-sheet aggregates involved in the pulmonary alveolar proteinosis (PAP).

    16
    Lysozyme
    Functions

    It is an enzyme occurring naturally in egg white, human tears, saliva, and other body fluids, capable of degrading peptidoglycane and thereby acting as a mild antiseptic.

    Pathologies

    Mutations in the lysozyme gene can lead to the aggregation of the human protein, therefore to non-neuropathic systemic amyloidosis.

    122
    Odontogenic ameloblast-associated protein


    0
    Prion Protein
    Functions

    Although the actual function of PrP remains unknown, many hypothesis are proposed, such as involvement in signal transmission or in copper regulation, as well as a possible function of copper-dependent superoxide dismutase.

    Pathologies

    PrP is the well-known prion protein of mammals. Its prionic form leads to many neurodegenerative diseases, including transmissible spongiform encephalopathies (scrapie in sheep, bovine spongiform encephalopathy in cattle or Creutzfeldt-Jacob disease and Gerstmann-Straussler-Scheinker syndrome in humans) and some dementias.

    353
    Prolactin
    Functions

    Prolactin is involved in a wide variety of biological processes, among wich are osmoregulation, development, reproduction, or immune regulation.

    Pathologies

    This hormone constitutes the amyloid fibrils of pituitary glands of aging individuals.

    112
    Semenogelin 1


    0
    Tau
    Functions

    Tau binds to and regulates the assembly and stability of neuronal microtubules.

    Pathologies

    Tau proteins are found in extracellular aggregates associated with Alzheimer's disease. Those proteins are also involved in many dementia, usually due to defects in the Tau gene.

    37
    Transthyretin
    Functions

    Transthyretin is a plasma protein that transports thyroxine. It can also form complexes with retinol binding proteins, so that those proteins are not lost by filtration in the kidney.

    Pathologies

    Single site mutations are associated with familial amyloid polyneuropathy (FAP). Those mutations destabilize tetrameric TTR, inducing monomeric amyloidogenic intermediates apparition. Those intermediates assembles into amyloid fibrils, whereas wild-type TTR remains tetrameric and nonamyloidogenic.

    54