Amyloid: Encyclopedia - Amyloid

Amyloid

Amyloid describes various types of protein aggregations that share specific traits when examined microscopically. 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, rather a deposition of proteinaceous mass.

Specifically, amyloid deposits are extracellular, thioflavin s positive, and exhibit apple-green birefringence when stained with congo red. Other indicators exist, such as serum amyloid p-component binding. Since these are indirect indicators, biophysicists have redefined amyloid using a canonical set of biophysical characteristics (see below), and this seems to cause a low level of conflict between histologists and biophysicists.

The phenotypes of genetically transmitted amyloid diseases are often inherited in an autosomal dominant fashion. Sometimes, the difference between aggressive amyloid diseases and senescent amyloid diseases is due to a mutation which makes the protein more prone to aggregation. Most commonly seen are point mutations which affect the cohesiveness of the protein and promote misfolding; other mutations cause aggregation-prone pieces of the protein to be cleaved off from the rest of the protein.

Amyloid - Diseases featuring amyloid

It should be noted that in almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or if they are instead a symptom downstream of a common ideopathic agent. The associated proteins are indicated in parentheses.

• Systemic amyloidosis
  • Primary amyloidosis
    • Mutations in lysozyme, transthyretin, apolipoprotein B, fibrinogen
  • Secondary amyloidosis
    • AA amyloidosis (amyloid A protein, an acute phase protein due to chronic inflammation)
    • AL amyloidosis (immunoglobulin light chains)
    • Gelsolin amyloidosis (plasma gelsolin fragments).
  • Familial or Hereditary amyloidosis
    • Most commonly caused by mutations in the transthyretin protein, but in rare occurrences can also be caused by apolipoprotein A1, gelsolin, fibrinogen, and lysozyme mutations.
    • Primarily caused by genetics, believed to be autosomal dominant, high probability of passage to offspring
    • Appalachian type amyloidosis is perhaps the most well known type
• Organ-specific amyloidosis
  • Diabetes mellitus type 2 (amylin, also known as IAPP)
  • Neurology
    • Alzheimer's disease (Aβ 39-42)
    • Parkinson's disease (alpha-synuclein) -- biophysical definition
    • Huntington's disease (huntingtin) -- biophysical definition
    • Spongiform encephalopathies
      • Creutzfeldt-Jakob disease (PrP in cerebrum)
      • Kuru (diffuse PrP deposits in brain)
      • Fatal Familial Insomnia (PrP in thalamus)
      • Bovine spongiform encephalopathy (PrP in cerebrum)
    • Congophilic angiopathy (Amyloid beta)
    • congestive heart failure; some instances (PrP in heart)
  • Inclusion body myositis
• Iatrogenic conditions
  • insulin amyloidosis (injection-administered insulin)

Amyloid - Non-disease amyloids

• Native amyloids in organisms
  • Curli E. coli Protein (curlin)
  • Malarial coat protein
  • Spider silk
  • Mammalian melanosomes (pMel)
• Proteins and peptides known to make amyloid without any known disease
  • Calcitonin
• Proteins and peptides engineered to make amyloid

Amyloid - Disease relation disputed

• • Yeast Prion [Sup35] {Ref Nakayashiki, PNAS, 2005}

Amyloid - Amyloid biophysics

The amyloid fold is characterized by a cross-beta sheet quaternary structure, that is, a monomeric unit contributes a beta strand to a beta sheet which spans across more than one molecule. 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 is amyloid is by placing a sample in an X-ray diffraction beam; there are two characteristic scattering bands produced at 4 and 10 angstroms (0.4 nm and 1.0 nm}, corresponding to the interstrand distances in the beta sheet structure.

Amyloid 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. Cross-polymerization is a phenomenon observed in vitro, and this is a putative mechanism explaining a link between diabetes and Alzheimer's disease. This is also the mechanism of prion propagation.

There are two broad classes of amyloid-forming polypeptide sequences. Poly-glutamine repeats, which are important in the amyloidogenesis of Yeast and mammalian prions, as well as huntiongton's disease. Poly-glutamines aggregate in a beta-sheet conformation, where the the structure is braced by hydrogen bonding from the glutamine amide. 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.

Amyloid - Histological staining

Amyloid is typically identified by a change in the fluorescence intensity of planar aromatic dyes such as Thioflavin T or Congo Red. This is generally attributed to the environmental change as these dyes intercolate between beta-strands. Congophillic amyloid plaques generally cause apple-green birefringence, when viewed through crossed polarimetric filters. To avoid nonspecific staining, histology stains, such as haematoxylin and eosin stain, are used to quench the dyes' activity in other places where the dye might bind, such as the nucleus. The dawn of 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.

Adapted from the Wikipedia article "Amyloid", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki