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

Abstract

Previous studies have shown that the amyloid localized to the aortic intima may be a biochemical entity different from other forms of localized amyloid. The amyloid fibril protein in one patient studied consisted of an N-terminal fragment of apolipoprotein A-1 (apo A-1). Since this patient was later shown to carry a missense mutation in the apo A-1 gene, leading to a deletion at position 107 of the mature protein, the question remained whether wild-type apo A-1 is amyloidogenic. In autopsy specimens from the thoracic aorta from 69 individuals, intimal atherosclerotic plaque-related amyloid was present in 11 cases (16%) and amyloid outside plaques in 37 cases (54%). The immunoreactivity of amyloid localized to the aortic intima was evaluated with the aid of antisera against N-terminal segments of apo A-1. The amyloid in association with atherosclerotic plaques was positively labelled by immunohistochemistry. The amyloid fibril protein from one patient, previously shown not to carry any mutation in the apo A-1 gene, was purified and shown by amino acid sequence analysis to be of apo A-1 nature. The result shows that wild-type apo A-1 is amyloidogenic and gives rise to a common localized form of amyloid associated with atherosclerosis.

Myeloperoxidase-mediated Methionine Oxidation Promotes an Amyloidogenic Outcome for Apolipoprotein A-I

“…Westermark et al (19,22,(25)(26)(27)(28)(29), a novel scenario is emerging in which wild-type apoA-I is the main component of amyloid fibrils isolated from, so far, lung nodules (21), knee joints (22), peripheral neural tissues (sciatic nerve) (23), aortic valves (24), aorta atherosclerotic plaques (25,26), and peripheral atherosclerotic plaques (27). Interestingly, in some cases, not only N-terminal fragments but full-length wild-type apoA-I was found in the amyloid fibrils extracted from clinical samples (23).…”

“…The high incidence of amyloid fibrils associated with aortic intima and with atherosclerotic lesions indicates that amyloid deposition in the intima may contribute to atherosclerosis progression (25,26,28,29); however, the extent of this contribution is yet to be demonstrated (27). The identification of apoA-I as the main component of atherosclerosis-associated amyloids suggests a link between local apoA-I oxidation and increased amyloidogenic potential of oxidized wild-type apoA-I.…”

Apolipoproteins and amyloid fibril formation in atherosclerosis

“…However, amyloid deposits of heterogeneous origin have also been detected in the intima, where they are commonly associated with atherosclerotic plaques (Howlett and Moore, 2006). In fact, recent studies suggest that fibrillar amyloid species may be present in up to 60% of aortic atherosclerotic lesions (Mucchiano et al, 2001a;Mucchiano et al, 2001b;Röcken et al, 2006).…”

“…Amyloid deposits in atherosclerosis appear to include amyloid fibrils derived from apoA-I (Westermark et al, 1995;Mucchiano et al, 2001a;Howlett and Moore, 2006). Despite being common, it is not known why apoA-I is deposited as amyloid specifically in atherosclerotic plaques; however these amyloid deposits are believed to be pathogenically linked to atherosclerosis progression.…”

Impact of Self-association on Function of Apolipoprotein A-I

“…Recently, a mechanistic link between apoA-I self-association and amyloidosis has been identified (46). In the atherosclerotic plaque tissue, deposition of apoA-I amyloids contributes to the mechanism of atherosclerosis progression (47,48). ApoA-I methionine oxidation (49) has been implicated in the formation of full-length apoA-I amyloid fibrils through a mechanism involving disruption of apoA-I self-association, reduction of conformational stability in solution, and higher propensity to protein misfolding and aggregation (46).…”