| 1. |
- Amarzguioui, Mohammed, et al.
(author)
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Extensive Intimal Apolipoprotein A1-Derived Amyloid Deposits in a Patient with an Apolipoprotein A1 Mutation
- 1998
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 242:3, s. 534-539
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Journal article (peer-reviewed)abstract
- In the aortic intima amyloid deposits are often associated with atherosclerotic plaques. In a recent study of one patient with aortic intimal amyloid the major fibril protein was an N-terminal fragment of apolipoprotein A1 (apoA1) consisting of 69 amino acid residues. In the present study, we have screened the apoA1 gene for mutations in autopsy cases with aortic intimal amyloid immunohistochemically positive for apoA1, using single stranded conformational polymorphism (SSCP) analysis and DNA sequencing. All cases except one had a normal apoA1 gene sequence. One case of exceptionally severe atherosclerosis combined with extensive intimal amyloid deposits showed an apoA1 deletion corresponding to Lys 107. Thus, wild type apoA1 is amyloidogenic but our findings suggest that the expression of a mutant apoA1-form may be associated with enhanced amyloidogenicity.
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| 2. |
- Mucchiano, Gerd, et al.
(author)
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Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta
- 2001
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In: Journal of Pathology. - 0022-3417 .- 1096-9896. ; 193:2, s. 270-275
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Journal article (peer-reviewed)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.
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| 3. |
- Mucchiano, Gerd
(author)
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Apolipoprotein A-1 derived amyloid in the atherosclerotic intima of the human aorta
- 2000
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 4. |
- Mucchiano, Gerd I., et al.
(author)
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Apolipoprotein A-I–Derived Amyloid in Atherosclerosis : Its Association With Plasma Levels of Apolipoprotein A-I and Cholesterol
- 2001
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In: American Journal of Clinical Pathology. - 0002-9173 .- 1943-7722. ; 115, s. 298-303
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Journal article (peer-reviewed)abstract
- Wild-type apolipoprotein A-I (apo A-I)–derived amyloid commonly occurs in atherosclerotic plaques. To clarify apo A-I amyloid formation, plasma levels of apo A-I and cholesterol were related to the presence of amyloid in atherosclerotic plaques in 15 patients with peripheral atherosclerosis, subjected to arterial reconstruction. Plasma levels of apo A-I and high-density lipoprotein (HDL) cholesterol were slightly higher in patients with apo A-I–derived amyloid than in those without, but the difference was not significant. Levels of low-density lipoprotein cholesterol and total cholesterol were significantly higher in the group with amyloid. High concentrations of apo A-I in the arterial intima are probably of greater importance to amyloid formation than high plasma levels of the protein. During atherosclerosis, the acute phase reactant serum amyloid A may displace apo A-I from HDL, leading to increased concentration of lipid-free apo A-I in the intima and conformational changes of apo A-I, which make it more fibrillogenic. Some forms of amyloid fibrils have been shown to be cytotoxic. Apo AI–derived amyloid is possibly a pathogenically important factor in atherosclerosis.
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| 5. |
- Mucchiano, Gerd, et al.
(author)
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Senile aortic amyloid : Evidence for two distinct forms of localized deposits
- 1992
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In: American Journal of Pathology. - 0002-9440 .- 1525-2191. ; 140:4, s. 871-877
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Journal article (peer-reviewed)abstract
- Aortic tissues obtained at autopsy were examined from 84 patients (age, 18-96 years). Amyloid deposits were present in the media in 61 of 63 (97%) of the patients above the age of 50. In addition, intimal amyloid deposits were present in 35% of this group. Intimal amyloid differed from medial amyloid both in its morphologic characteristics and its association with atherosclerosis. An antiserum raised to a low molecular weight protein extracted from amyloid fibrils of the aortic media reacted specifically with medial amyloid but did not react with intimal deposits. Neither type of amyloid reacted with anti-ATTR (Senile systemic amyloid), anti-AANF (isolated atrial amyloid), or antisera to other known forms of amyloid. These findings are consistent with the presence of two separate forms of localized amyloid in the aging aorta.
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| 6. |
- Westermark, Per, et al.
(author)
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Apolipoprotein A1-derived amyloid in human aortic atherosclerotic plaques
- 1995
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In: American Journal of Pathology. - 0002-9440 .- 1525-2191. ; 147:5, s. 1186-1192
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Journal article (peer-reviewed)abstract
- Amyloid deposits in the aortic intima are very common in association with atherosclerosis and aging. In the present study, a major fibril protein purified from amyloid present in human atherosclerotic plaques was shown to be a 69-amino acid N-terminal fragment of apolipoprotein AI. Although senile form of localized apolipoprotein AI-derived amyloidosis has recently been documented in pulmonary vessels of dogs, this is the first example of a localized human amyloid derived from this apolipoprotein.
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