Lipid-Induced β-Amyloid Peptide Assemblage Fragmentation

Widenbrant, Martin J. O.; Rajadas, Jayakumar; Sutardja, Christopher; Fuller, Gerald G.

doi:10.1529/biophysj.106.085944

Cited by 43 publications

(34 citation statements)

References 55 publications

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“…Because A␤ oligomers are basically hydrophilic and do not settle well on graphite (15), we conclude that A␤ rafts are formed by a previously undescribed hydrophobic oligomeric species. TEM and AFM studies performed with artificial membranes have shown that, upon interaction with the membrane lipids, A␤ in fibrillar form reverts to globular peptide oligomers that associate into disordered domains (55). Thus, raft-forming oligomers could be part of a physiologically relevant pathway leading to the incorporation of soluble A␤ into cell membranes.…”

Section: Discussionmentioning

confidence: 99%

Sulfated Polysaccharides Promote the Assembly of Amyloid β1–42 Peptide into Stable Fibrils of Reduced Cytotoxicity

Bravo

Arimon

Valle‐Delgado

et al. 2008

Journal of Biological Chemistry

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The histopathological hallmarks of Alzheimer disease are the self-aggregation of the amyloid ␤ peptide (A␤) in extracellular amyloid fibrils and the formation of intraneuronal Tau filaments, but a convincing mechanism connecting both processes has yet to be provided. Here we show that the endogenous polysaccharide chondroitin sulfate B (CSB) promotes the formation of fibrillar structures of the 42-residue fragment, A␤ 1-42 . Atomic force microscopy visualization, thioflavin T fluorescence, CD measurements, and cell viability assays indicate that CSB-induced fibrils are highly stable entities with abundant ␤-sheet structure that have little toxicity for neuroblastoma cells. We propose a wedged cylinder model for A␤ 1-42 fibrils that is consistent with the majority of available data, it is an energetically favorable assembly that minimizes the exposure of hydrophobic areas, and it explains why fibrils do not grow in thickness. Fluorescence measurements of the effect of different A␤ 1-42 species on Ca 2؉ homeostasis show that weakly structured nodular fibrils, but not CSB-induced smooth fibrils, trigger a rise in cytosolic Ca 2؉ that depends on the presence of both extracellular and intracellular stocks. In vitro assays indicate that such transient, local Ca 2؉ increases can have a direct effect in promoting the formation of Tau filaments similar to those isolated from Alzheimer disease brains. Pathogenesis in Alzheimer disease (AD)3 is linked to the accumulation of the highly amyloidogenic self-associating amyloid ␤ peptide (A␤). The amyloid cascade hypothesis postulates that AD pathology is initiated by an extracellular accumulation of A␤ that in turn triggers a transmembrane signal having as ultimate effect the formation of neurofibrillary tangles by the microtubule-associated protein Tau (1-3), followed by collapse of the microtubular cytoskeleton. Some of the mechanisms that have been proposed to explain how extracellular A␤ exerts its cytotoxic effects include the promotion of oxidative stress (4

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Section: Discussionmentioning

confidence: 99%

Sulfated Polysaccharides Promote the Assembly of Amyloid β1–42 Peptide into Stable Fibrils of Reduced Cytotoxicity

Bravo

Arimon

Valle‐Delgado

et al. 2008

Journal of Biological Chemistry

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“…[57,58,59] It has been widely accepted that, depending on environmental conditions, such as pH, concentration, temperature, ionic strength, metal ions, and so forth, monomeric Ab can undergo a conformational change to form partially structured intermediates susceptible to fibril formation by a nucleation and growth process. [5,60] In this work, we determined the structures of AbA C H T U N G T R E N N U N G (1-40) in aqueous HFIP solutions at different pH, that has been reported as a model system for aggregation studies.…”

Section: Discussionmentioning

confidence: 99%

pH Effects on the Conformational Preferences of Amyloid β‐Peptide (1–40) in HFIP Aqueous Solution by NMR Spectroscopy

et al. 2008

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The structure and aggregation state of amyloid beta-peptide (Abeta) in membrane-like environments are important determinants of pathological events in Alzheimer's disease. In fact, the neurotoxic nature of amyloid-forming peptides and proteins is associated with specific conformational transitions proximal to the membrane. Under certain conditions, the Abeta peptide undergoes a conformational change that brings the peptide in solution to a "competent state" for aggregation. Conversion can be obtained at medium pH (5.0-6.0), and in vivo this appears to take place in the endocytic pathway. The combined use of (1)H NMR spectroscopy and molecular dynamics-simulated annealing calculations in aqueous hexafluoroisopropanol simulating the membrane environment, at different pH conditions, enabled us to get some insights into the aggregation process of Abeta, confirming our previous hypotheses of a relationship between conformational flexibility and aggregation propensity. The conformational space of the peptide was explored by means of an innovative use of principal component analysis as applied to residue-by-residue root-mean-square deviations values from a reference structure. This procedure allowed us to identify the aggregation-prone regions of the peptide.

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“…The peptide is affecting physicochemical properties of the membrane and, in turn, the membrane is affecting aggregations features of the peptide, hence neurodegeneration [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Abeta Peptide Toxicity is Reduced After Treatments Decreasing Phosphatidylethanolamine Content in Differentiated Neuroblastoma Cells

et al. 2011

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We investigated whether the toxicity of oligomeric amyloid-beta peptide (Abeta1-42) upon differentiated human neuroblastoma SH-SY5Y cells, can be affected by changes of membrane lipid composition. An immunostaining technique, using lipids extracted from the cells and separated by thin layer chromatography, suggested that Abeta preferentially binds to phosphatidylethanolamine (PE), one of the major lipids in the cell extract. For this reason, we utilized treatments with putative inhibitors of phosphatidylethanolamine biosynthesis (choline, phosphocholine, R59949) to decrease its proportion in the cell membrane; choline treatment (2.5 mM, 24 h) showed the best performance, reducing phosphatidylethanolamine content from 5.7 to 3.3 μg phosphorous/mg protein. Either the extent of Abeta binding or its toxicity decreased onto choline-treated cells. These data may open the possibility to develop future strategies aiming to reduce Abeta toxicity in Alzheimer disease.

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Lipid-Induced β-Amyloid Peptide Assemblage Fragmentation

Cited by 43 publications

References 55 publications

Sulfated Polysaccharides Promote the Assembly of Amyloid β1–42 Peptide into Stable Fibrils of Reduced Cytotoxicity

Sulfated Polysaccharides Promote the Assembly of Amyloid β1–42 Peptide into Stable Fibrils of Reduced Cytotoxicity

pH Effects on the Conformational Preferences of Amyloid β‐Peptide (1–40) in HFIP Aqueous Solution by NMR Spectroscopy

Abeta Peptide Toxicity is Reduced After Treatments Decreasing Phosphatidylethanolamine Content in Differentiated Neuroblastoma Cells

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