Apolipoprotein A-1 derived amyloid in the atherosclerotic intima of the human aorta

• Amyloid is insoluble fibrillar protein deposited in the extracellular space. The resulting heterogeneous group of disorders, amyloidosis, can be sporadic or hereditary, and the amyloid is systemically distributed or localized in single organs. Systemic hereditary amyloidoses are disorders caused by mutant forms of plasma proteins such as transthyretin (TTR) or less frequently, apolipoprotein A-1 (apo A-1), the major protein in high-density lipoprotein (HDL). Local deposition of amyloid associated with aging may be pathogenically important in Alzheimer's disease and type II diabetes. Localized amyloid in the medial and intimal layer of the aorta, commonly found in elderly humans, is of unknown sigoificance. The aim of this work was to investigate the nature of amyloid in the atherosclerotic intima of the human aorta, its fibrillogenesis and potential pathogenic importance. Two biochemically different forms of localized amyloid deposits in the aorta were identified; one affecting the atherosclerotic plaques of the intima and the other the media. Amyloid fibrils from the media has subse quently been found to consist of a protein fragment derived from lactadherin. Purified amyloid protein from atherosclerotic plaques of aortas in utopsy cases was shown by amino acid sequence analysis to be derived from apo A-1. Apo A-1 derived amyloid was immunohistochemically confirmed in 14% of 72 autopsy cases. A mutation was found in the apo A-1 gene (Δ Lys 1 07) in one of the 9 cases with intimal amyloid. Thus wild type, as well as mutant apo A-1, is amyloidogenic in humans. There was a tendency towards higher plasma levels of apo A-1 in patients with apo A-1 derived amyloid who underwent arterial reconstruction, compared to those without amyloid (p= 0.055). Levels of LDL- and total cholesterol were higher in the group with amyloid. Atherosclerosis induces high concentration of the acute phase reactant SAA in atherosclerotic lesions. SAA may displace apo A-1 from HDL, which, in addition to high levels of plasma apo A-1, could lead to an increased concentration oflipid free apo A-1 in the intima. Conformational changes in apo A-1 are then induced, making it more prone to fibril formation. Since some forms of amyloid fibrils are known to be cytotoxic, apo A-1 derived amyloid may contribute to the injury caused by other factors in atherosclerotic lesions.

Nyckelord

MEDICINE

MEDICIN

Publikations- och innehållstyp

vet (ämneskategori)

dok (ämneskategori)