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Cellular mechanism of fibril formation from serum amyloid A1 protein.

ABSTRACT: Serum amyloid A1 (SAA1) is an apolipoprotein that binds to the high-density lipoprotein (HDL) fraction of the serum and constitutes the fibril precursor protein in systemic AA amyloidosis. We here show that HDL binding blocks fibril formation from soluble SAA1 protein, whereas internalization into mononuclear phagocytes leads to the formation of amyloid. SAA1 aggregation in the cell model disturbs the integrity of vesicular membranes and leads to lysosomal leakage and apoptotic death. The formed amyloid becomes deposited outside the cell where it can seed the fibrillation of extracellular SAA1. Our data imply that cells are transiently required in the amyloidogenic cascade and promote the initial nucleation of the deposits. This mechanism reconciles previous evidence for the extracellular location of deposits and amyloid precursor protein with observations the cells are crucial for the formation of amyloid.

SUBMITTER: Claus S

PROVIDER: S-EPMC5538634 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Cellular mechanism of fibril formation from serum amyloid A1 protein.

Claus Stephanie S Meinhardt Katrin K Aumüller Tobias T Puscalau-Girtu Ioana I Linder Julia J Haupt Christian C Walther Paul P Syrovets Tatiana T Simmet Thomas T Fändrich Marcus M

EMBO reports 20170621 8

Serum amyloid A1 (SAA1) is an apolipoprotein that binds to the high-density lipoprotein (HDL) fraction of the serum and constitutes the fibril precursor protein in systemic AA amyloidosis. We here show that HDL binding blocks fibril formation from soluble SAA1 protein, whereas internalization into mononuclear phagocytes leads to the formation of amyloid. SAA1 aggregation in the cell model disturbs the integrity of vesicular membranes and leads to lysosomal leakage and apoptotic death. The formed ...[more]

PMID: 28637682

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