scholarly journals Cross-Seeding and Cross-Competition in Mouse Apolipoprotein A-II Amyloid Fibrils and Protein A Amyloid Fibrils

2007 ◽  
Vol 171 (1) ◽  
pp. 172-180 ◽  
Author(s):  
Jingmin Yan ◽  
Xiaoying Fu ◽  
Fengxia Ge ◽  
Beiru Zhang ◽  
Junjie Yao ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Protein A ◽  
Apolipoprotein A ◽  
Cross Competition

scholarly journals Formation of Toxic Amyloid Fibrils by Amyloidβ-Protein on Ganglioside Clusters

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Katsumi Matsuzaki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physicochemical Properties ◽  
Lipid Rafts ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Protein A ◽  
Pivotal Role ◽  
Membrane Interaction

It is widely accepted that the conversion of the soluble, nontoxic amyloidβ-protein (Aβ) monomer to aggregated toxic Aβrich inβ-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβin vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβaggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβamyloids formed in solution. Furthermore, differences between Aβ-(1–40) and Aβ-(1–42) in membrane interaction and amyloidogenesis are also emphasized.

Amyloid fibrils formed by selective N- and C-terminal sequences of mouse apolipoprotein A-II

Amyloid ◽  
2011 ◽  
Vol 18 (sup1) ◽  
pp. 19-21 ◽  
Author(s):  
J. Sawashita ◽  
F. Kametani ◽  
K. Hasegawa ◽  
M. Mori ◽  
H. Naiki ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Apolipoprotein A

Abstract 539: Soluble Oxidized Apolipoprotein A-I, a Precursor of Amyloid Fibrils, Activates Secretion of Inflammatory Cytokines in Macrophages

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Andrzej Witkowski ◽  
Gary K Chan ◽  
Nancy J Li ◽  
Rui Lu ◽  
Shinji Yokoyama ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Amyloid Fibrils ◽  
Mouse Bone Marrow ◽  
Amyloid Formation ◽  
Cellular Cholesterol ◽  
Atherosclerosis Progression ◽  
Apolipoprotein A ◽  
Inflammatory Protein ◽  
Release Capacity

Atherosclerosis is often described as an inflammatory disease of the arteries. One mechanism whereby apolipoprotein A-I (apoA-I) exerts its anti-atherosclerotic effect is by mitigating the inflammatory response of cells involved in atherosclerosis progression. However, oxidation transforms apoA-I from an anti-inflammatory to a pro-inflammatory protein. We previously reported that oxidation can also promote apoA-I aggregation and formation of amyloid fibrils. In this study, we investigated the mechanistic interplay between oxidation, amyloid formation and the inflammatory response of macrophages to apoA-I. We hypothesized that amyloid fibrils constituted of oxidized apoA-I activate production of inflammatory cytokines in macrophages. To test this hypothesis, amyloidogenic apoA-I was generated by oxidation with an excess of H 2 O 2 (H 2 O 2 -ApoA-I). Intracellular and secreted levels of IL-1β were determined upon incubation of mouse bone marrow derived macrophages (BMDM) with intact-apoA-I, soluble H 2 O 2 -ApoA-I and pre-formed H 2 O 2 -ApoA-I amyloid fibrils. Cellular cholesterol release from RAW264.7 cells was also measured. Soluble H 2 O 2 -ApoA-I (amyloid precursor) retained the cellular cholesterol release capacity of intact-ApoA-I. In BMDM incubated with soluble H 2 O 2 -ApoA-I however, levels of IL-1β synthesis and secretion were at least 2-fold higher than those induced by intact-ApoA-I. In contrast, incubation with H 2 O 2 -ApoA-I amyloid fibrils did not increase the levels of IL-1β synthesis and secretion, compared to intact-ApoA-I. Thus, soluble and functional oxidized apoA-I activates inflammatory cytokine synthesis and secretion in macrophages. Notably, this pro-inflammatory potential was completely neutralized when oxidized apoA-I was aggregated in amyloids. Therefore in atherosclerotic lesions, amyloid formation could reduce, rather than exacerbate, the inflammatory burden produced by pro-inflammatory soluble oxidized apoA-I species.

scholarly journals Highly repeated sites in the apolipoprotein(a) gene recognized by methylated DNA-binding protein, a sequence-specific DNA-binding protein.

1990 ◽  
Vol 10 (9) ◽  
pp. 4957-4960 ◽  
Author(s):  
K C Ehrlich ◽  
M Ehrlich
Keyword(s):  
Risk Factor ◽  
Dna Binding ◽  
Binding Protein ◽  
Protein A ◽  
Dna Binding Protein ◽  
High Plasma ◽  
Methylated Dna ◽  
Human Apolipoprotein ◽  
Apolipoprotein A ◽  
Lower Molecular Mass

Methylated DNA-binding protein (MDBP), a sequence-specific DNA-binding protein, was found to recognize more than 30 sites within an allele of the human apolipoprotein(a) gene. High plasma levels of apolipoprotein(a), a risk factor for atherosclerosis, have been correlated with genetically inherited lower-molecular-mass isoforms of this protein. MDBP might help down modulate the expression of the apolipoprotein(a) gene in a manner dependent on the length of a given allele of the gene and the number of MDBP sites in it.

The molecular interaction of 4′-iodo-4′-deoxydoxorubicin with Leu-55Pro transthyretin ‘amyloid-like’ oligomer leading to disaggregation

2000 ◽  
Vol 351 (1) ◽  
pp. 273-279 ◽  
Author(s):  
Maria Paula SEBASTIÃO ◽  
Giampaolo MERLINI ◽  
Maria João SARAIVA ◽  
Ana Margarida DAMAS
Keyword(s):  
Iodine Atom ◽  
Amyloid Fibrils ◽  
Protein A ◽  
Intermediate Structure ◽  
Biochemical Pathway ◽  
Wild Type ◽  
Immunoglobulin Light Chain ◽  
Amyloid Load ◽  
Β Sheets ◽  
Immunoglobulin Light Chain Amyloidosis

The crystal structure of the amyloidogenic Leu-55Pro transthyretin (TTR) variant has revealed an oligomer structure that may represent a putative amyloid protofibril [Sebastião, Saraiva and Damas (1998) J. Biol. Chem. 273, 24715–24722]. Here we report biochemical evidence that corroborates the isolation of an intermediate structure, an ‘amyloid-like’ oligomer, which is most probably present in the biochemical pathway that leads to amyloid deposition and that was isolated by the crystallization of the Leu-55Pro TTR variant. 4´-Iodo-4´-deoxydoxorubicin (IDOX) is a compound that interacts with amyloid fibrils of various compositions and it has been reported to reduce the amyloid load in immunoglobulin light chain amyloidosis [Merlini, Ascari, Amboldi, Bellotti, Arbustini, Perfetti, Ferrari, Zorzoli, Marinone, Garini et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 2959–2963]. In this work, we observed that the monoclinic Leu-55Pro TTR crystals, soaked with IDOX, undergo rapid dissociation. Moreover, under the same conditions, the orthorhombic wild-type TTR crystals are quite stable. This is explained by the different TTR conformations isolated upon crystallization of the two proteins; while the Leu-55Pro TTR exhibits the necessary conformation for IDOX binding, the same structure is not present in the crystallized wild-type protein. A theoretical model concerning the interaction of Leu-55Pro TTR with IDOX, which is consistent with the dissociation of the amyloid-like oligomer, is presented. In this model the IDOX iodine atom is buried in a pocket located between the two β-sheets of the Leu-55Pro TTR monomer with the IDOX aromatic-moiety long axis nearly perpendicular to the direction of the β-sheets.

scholarly journals Accumulation of pro-apolipoprotein A-II in mouse senile amyloid fibrils

1997 ◽  
Vol 325 (3) ◽  
pp. 653-659 ◽  
Author(s):  
Keiichi HIGUCHI ◽  
Kumiko KOGISHI ◽  
Jing WANG ◽  
Chen XIA ◽  
Takuya CHIBA ◽  
...  
Keyword(s):  
Amino Acid ◽  
High Density Lipoprotein ◽  
Relative Abundance ◽  
Mouse Liver ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Density Lipoprotein ◽  
Amyloid Protein ◽  
Amino Acid Residues ◽  
Apolipoprotein A

Apolipoprotein A-II (apoA-II), the major apoprotein of serum high-density lipoprotein, is deposited as amyloid fibrils (AApoAII) in murine senile amyloidosis. We have identified and purified a more basic amyloid protein from old-mouse liver. N-terminal sequencing of the protein revealed that the pro-segment of five amino acid residues (Ala-Leu-Val-Lys-Arg) extended from the N-terminal glutamine residue of mature apoA-II protein. MS analysis revealed the deposit of intact pro-apoA-II protein (molecular mass 9319 Da). Antiserum was prepared for staining of the AApoAII amyloid deposition. The relative abundance of pro-apoA-II to mature apoA-II in the amyloid-fibril fraction isolated from livers of mice with severe amyloidosis was 14.1%. The similar abundance of pro-apoA-II in the amyloid fibril fraction from the spleen (16.3%) suggested that deposited pro-apoA-II originated from the blood. The concentration of pro-apoA-II was much lower in the serum (1.5% of mature apoA-II) than in the amyloid-fibril fraction. There was no difference in the content of pro-apoA-II between the amyloidogenetic R1.P1-Apoa2c and amyloid-resistant SAMR1 strains at the age of 3 months. The abundance of pro-apoA-II in the amyloid-fibril fraction compared with the serum suggested that it plays a key role in the initialization of mouse senile amyloidosis.

scholarly journals Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

2015 ◽  
Vol 290 (34) ◽  
pp. 20947-20959 ◽  
Author(s):  
Chiharu Mizuguchi ◽  
Fuka Ogata ◽  
Shiho Mikawa ◽  
Kohei Tsuji ◽  
Teruhiko Baba ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Amyloid Fibrils ◽  
Helical Structure ◽  
Lipid Binding ◽  
Fibril Formation ◽  
Random Coil ◽  
Helical Conformation ◽  
Apolipoprotein A ◽  
Terminal Fragment ◽  
Lipid Environment

The N-terminal amino acid 1–83 fragment of apolipoprotein A-I (apoA-I) has a strong propensity to form amyloid fibrils at physiological neutral pH. Because apoA-I has an ability to bind to lipid membranes, we examined the effects of the lipid environment on fibril-forming properties of the N-terminal fragment of apoA-I variants. Thioflavin T fluorescence assay as well as fluorescence and transmission microscopies revealed that upon lipid binding, fibril formation by apoA-I 1–83 is strongly inhibited, whereas the G26R mutant still retains the ability to form fibrils. Such distinct effects of lipid binding on fibril formation were also observed for the amyloidogenic prone region-containing peptides, apoA-I 8–33 and 8–33/G26R. This amyloidogenic region shifts from random coil to α-helical structure upon lipid binding. The G26R mutation appears to prevent this helix transition because lower helical propensity and more solvent-exposed conformation of the G26R variant upon lipid binding were observed in the apoA-I 1–83 fragment and 8–33 peptide. With a partially α-helical conformation induced by the presence of 2,2,2-trifluoroethanol, fibril formation by apoA-I 1–83 was strongly inhibited, whereas the G26R variant can form amyloid fibrils. These findings suggest a new possible pathway for amyloid fibril formation by the N-terminal fragment of apoA-I variants: the amyloidogenic mutations partially destabilize the α-helical structure formed upon association with lipid membranes, resulting in physiologically relevant conformations that allow fibril formation.

scholarly journals Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease

1993 ◽  
Vol 90 (23) ◽  
pp. 11282-11286 ◽  
Author(s):  
K Uéda ◽  
H Fukushima ◽  
E Masliah ◽  
Y Xia ◽  
A Iwai ◽  
...  
Keyword(s):  
Amino Acid ◽  
Alzheimer Disease ◽  
Amyloid Fibrils ◽  
Protein A ◽  
Microscopic Analysis ◽  
Amino Acid Sequences ◽  
Full Length ◽  
Peptide Sequence ◽  
Electron Microscopic ◽  
Hydrophobic Domain

A neuropathological hallmark of Alzheimer disease (AD) is a widespread amyloid deposition. We analyzed the entire amino acid sequences in an amyloid preparation and found, in addition to the major beta/A4-protein (A beta) fragment, two unknown peptides. We raised antibodies against synthetic peptides using subsequences of these peptides. These antibodies immunostained amyloid in neuritic and diffuse plaques as well as vascular amyloid. Electron microscopic analysis demonstrated that the immunostaining was localized on amyloid fibrils. We have isolated an apparently full-length cDNA encoding a 140-amino-acid protein within which two previously unreported amyloid sequences are encoded in tandem in the most hydrophobic domain. We tentatively named this 35-amino acid peptide NAC (non-A beta component of AD amyloid) and its precursor NACP. NAC is the second component, after A beta, identified chemically in the purified AD amyloid preparation. Secondary structure predictions indicate that the NAC peptide sequence has a strong tendency to form beta-structures consistent with its association with amyloid. NACP is detected as a M(r) 19,000 protein in the cytosolic fraction of brain homogenates and comigrates on immunoblots with NACP synthesized in Escherichia coli from NACP cDNA. NACP mRNA is expressed principally in brain but is also expressed in low concentrations in all tissues examined except in liver, suggesting its ubiquitous and brain-specific functions. The availability of the cDNA encoding full-length NACP should help to elucidate the mechanisms of amyloidosis in AD.

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