Serum amyloid A (SAA)-derived amyloid AA is the systemic amyloid deposited in reactive (secondary) amyloidosis. SAA is an acute phase protein. Which statement about the mechanism of AA amyloid formation is MOST accurate?

• A SAA undergoes glycation in chronic inflammatory states, with advanced glycation end products cross-linking SAA to form irreversible amyloid
• B Sustained elevation of SAA (a normal alpha-helix-rich apolipoprotein) causes its conversion to beta-pleated sheet conformation due to partial proteolysis by serum proteases, generating AA fibrils that deposit in spleen, liver, and kidneys ✓
• C IL-1-mediated phosphorylation of SAA exposes a cryptic amyloidogenic peptide sequence recognized by TLR4 on macrophages
• D SAA amyloid formation requires interaction with serum amyloid P component (SAP), which acts as a chaperone to nucleate fibrils exclusively in the glomerular mesangium

Explanation

SAA is normally synthesized in the liver as an alpha-helix-rich apolipoprotein that associates with HDL. During sustained acute phase responses (in rheumatoid arthritis, chronic infections, periodic fever syndromes), persistently elevated SAA is partially degraded by neutral proteases (particularly in macrophages), generating AA fragments (the N-terminal 76-amino acid fragment) that are conformationally unstable and spontaneously misfold into beta-pleated sheet structures, self-aggregate into amyloid fibrils, and deposit in kidney (glomeruli and vessels), spleen, liver, and adrenals. SAP is a pentraxin that coats amyloid deposits and protects them from degradation but does not nucleate fibril formation. Glycation and TLR4 signalling are not the amyloidogenic mechanism.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.