The exact mechanism of fibril formation is unknown and may be different among the various types of amyloid.
Amyloid precursor proteins typically consist of long fibrils composed of relatively small precursor proteins with molecular weights between 4,000 and 25,000 daltons.
Each amyloid fibril protein has a precursor molecule in the serum.
— The secondary structures of many of the proteins have substantial β-pleated sheet structure. The known exceptions include serum amyloid A (SAA) and cellular prion protein (PrPc), which contain little or no β folding in the precursor protein despite extensive β-sheet in the deposited fibrils.
Amyloid formation involves:
— Stimulus-generated change in the serum concentration or primary structure of amyloid precursor proteins.
— Conversion of the precursor protein to amyloid fibrils.
In some cases, the aberrant secondary structure seen in amyloid formation reflects a hereditary alteration in amino acid sequence that predisposes to fibril formation.
— Examples include TTR, lysozyme, fibrinogen, cystatin c, gelsolin, amyloid-β protein precursor (AβPP), or apolipoprotein A-I (ApoA1).
In other cases, wild-type molecules are the fibril precursor.
— Examples include immunoglobulin light chain, β2-microglobulin, ApoA1, and others.
Several major proteins can form amyloid fibrils.
AL protein (immunoglobulin light chain):
— AL amyloidosis is usually caused by a plasma cell neoplasm in the marrow and can occur in isolation or along with myeloma (see Chap. 69).
— Myeloid fibril deposits are composed of intact 23-kDa monoclonal immunoglobulin light chains.
— Although all kappa (κ) and lambda (λ) light-chain subtypes have been identified in amyloid fibrils, λ subtypes predominate.
— λ VI subtype appears to have unique structural properties that predispose it to fibril formation, often in the kidney.
AL amyloidosis can be seen in other B lymphoproliferative disorders, including macroglobulinemia and lymphoma.
AL amyloidosis should be distinguished from nonamyloid monoclonal immunoglobulin deposition disease (MIDD), in which the deposited immunoglobulin consists of both heavy and light chains, of which κ chains predominate.
AA proteins (amyloid A proteins):
— AA amyloidosis occurs in response to inflammation and as a familial syndrome.
— The AA amyloid fibrils are usually composed of an 8-kDa, 76-amino-acid amino-terminal portion of the 12-kDa precursor, SAA.
— SAA is a polymorphic protein encoded by a family of active serum amyloid A (SAA) genes, which are acute phase apoproteins synthesized in the liver and transported by high-density lipoprotein (HDL3) in the plasma.
— Years of an underlying inflammatory disease causing an elevated SAA usually precedes fibril formation.
ATTR proteins (transthyretin):
— Occurs in several familial syndromes and in senile amyloid.
— ATTR amyloidosis also is known as familial amyloidotic polyneuropathy or cardiomyopathy.
— Variant TTR molecules are prone to dissociation from stable tetramers and to unfolding, leading to misfolding, polymerization, and fibril formation.
— Evidence of an age-related "trigger" is that senile cardiac amyloidosis, caused by the deposition of fibrils derived from normal wild-type TTR, is exclusively a disease of older people.
— Occurs in chronic hemodialysis patients.
— Carpal tunnel and joint synovial membrane involvement is common.
AP protein (P component):
— A minor protein component of amyloid deposits.
— Intravenously injected purified P component preferentially binds to amyloid deposits.
— This property has been exploited clinically, using radiolabeled P component, to localize and quantify the total body burden of amyloid in the so-called serum amyloid P (SAP) scan.
— Has structural homology with C-reactive protein.
Apo E allele (Apo E4):
— Strongly associated with Alzheimer disease.
In some instances, the amyloid precursors undergo proteolysis, which may enhance the kinetics of folding into a prefibrillar structural intermediate.
In some of the amyloidoses (e.g., Aβ or AA), a normal proteolytic process may be disturbed, yielding a higher than normal concentration of a prefibrillar molecule.