Human Apolipoprotein A-I-Derived Amyloid: Its Association with Atherosclerosis

Abstract

Amyloidoses constitute a group of diseases in which soluble proteins aggregate and deposit extracellularly in tissues. Nonhereditary apolipoprotein A-I (apoA-I) amyloid is characterized by deposits of nonvariant protein in atherosclerotic arteries. Despite being common, little is known about the pathogenesis and significance of apoA-I deposition. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of apoA-I. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements, thus favoring protein deposition as amyloid like-complexes. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce non hereditary amyloidosis as a consequence of the pro-inflammatory microenvironment associated to atherogenesis.

Dual Role of an N-terminal Amyloidogenic Mutation in Apolipoprotein A-I

“…We also found that the amyloid fibrils of the 1-83 fragments exhibit strong toxicity to HEK293 cells as with amyloid ␤ fibrils (40). To our knowledge, the finding that the 1-83 fragment of apoA-I forms amyloid fibrils at physiological neutral pH is quite novel because the previous observations indicated that the fibril formation of apoA-I in vitro requires the acidic condition (16,41,42), methionine oxidation (19), or amyloidogenic mutations (23,43).…”

Cellular Interaction and Cytotoxicity of the Iowa Mutation of Apolipoprotein A-I (ApoA-IIowa) Amyloid Mediated by Sulfate Moieties of Heparan Sulfate

“…We and others showed that HS mediated the cellular uptake of A␤ and the cellular association with A␤ (29,30). With regard to apoA-I amyloidosis, Ramella et al (31) reported that apoA-I interacted with heparin at acidic pH. However, involvement of HS in the pathological processes of apoA-I amyloidosis remains to be elucidated.…”

Amyloid-Forming Properties of Human Apolipoproteins: Sequence Analyses and Structural Insights

“…Human apoE4 isoform is a major causative risk factor in Alzheimer’s and other neurodegenerative diseases (Mahley et al 2009; Huang 2010; Hauser et al 2011). Another important plasma apolipoprotein, apoA-I, commonly deposits as fibrils in atherosclerotic plaques in a process that probably contributes to atherosclerosis (Mucchiano et al 2001; Röcken et al 2006; Howlett and Moore 2006; Teoh et al 2011a; Ramella et al 2011). Moreover, in a rare hereditary form of apoA-I amyloidosis, the N-terminal fragments of apoA-I deposit as fibrils in vital organs (kidneys, liver, heart, etc.)…”

“…Acquired amyloidosis is the most common form where full-length non-variant apoA-I deposits as fibers in arteries and tissues (Röcken et al 2006; Howlett and Moore 2006; Ramella et al 2011). Such fibrils were found in aortic plaques of >50 % of patients who underwent atherectomy (Mucciano et al 2001; Röcken et al 2006).…”