Where do the amyloid proteins come from

Where do the amyloid proteins come from and why does amyloid deposition occur?

Fibrillar amyloid proteins are derived from either an intact protein or a fragment of a larger precursor molecule. Circulating forms of the relevant proteins that deposit and form amyloid fibrils are responsible for systemic forms of amyloidosis, whereas local production of protein subunits that are precursors to amyloid fibril formation are responsible for localized or organ-specific amyloidosis. There are four circumstances that predispose to amyloid deposition:

  • • Sustained high concentrations of normal proteins (i.e., serum amyloid A [SAA] in chronic inflammation and β2-microglobulin in renal failure)
  • • Exposure to normal concentrations of a weakly amyloidogenic protein over a prolonged period (i.e., amyloid β-protein in Alzheimer’s disease)
  • • Acquired protein with an amyloidogenic structure (i.e., monoclonal immunoglobulin light chains in AL amyloid)
  • • Inherited variant protein with an amyloidogenic structure (i.e., TTR, others).

The pathogenesis of why certain proteins are capable of forming amyloid fibrils is unclear. Genetic factors are important in that mutations in certain proteins that circulate normally in plasma can result in structural changes that predispose them to undergo conformational changes leading to the formation of an antiparallel beta-pleated sheet configuration when the protein deposits in the tissue. Indeed, certain protein variants are known to be “amyloidogenic” and may be more susceptible to the processing that leads to amyloidosis. For example, in systemic AL amyloidosis, the immunoglobulin light chain λ VI is highly associated with amyloidosis, whereas the more common κ light chains are not. In systemic AA amyloid, certain phenotypes of SAA are more likely to form amyloid, whereas in hereditary systemic amyloidosis single amino acid variants of TTR are most commonly found. Finally, in addition to these amyloidogenic precursor proteins undergoing misfolding, SAP and certain GAGs may contribute to the seeding, aggregation, and deposition of amyloid in tissues. Notably, little tissue reaction occurs around amyloid, and once deposited, amyloid resists proteolysis and phagocytosis. Features of the precursor proteins and/or host factors could result in abnormal processing by mononuclear phagocytic cells or ineffective degradation.

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