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Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Department of Biochemistry and Biotechnology Center of Oslo, University of Oslo, Norway.
Department of Genetics and Pathology, Uppsala University, Sweden.
2001 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 193, no 2, 270-275 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2001. Vol. 193, no 2, 270-275 p.
Keyword [en]
amyloid, aorta, intima, apolipoprotein A-1, atherosclerosis, immunocytochemistry
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25966DOI: 10.1002/1096-9896(2000)9999:9999<::AID-PATH753>3.0.CO;2-SLocal ID: 10414OAI: oai:DiVA.org:liu-25966DiVA: diva2:246514
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Apolipoprotein A-1 derived amyloid in the atherosclerotic intima of the human aorta
Open this publication in new window or tab >>Apolipoprotein A-1 derived amyloid in the atherosclerotic intima of the human aorta
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2000. 74 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 636
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28611 (URN)13766 (Local ID)91-7219-737-4 (ISBN)13766 (Archive number)13766 (OAI)
Public defence
2000-09-15, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-08-13Bibliographically approved

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