Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity Export

@article{citeulike:6074540, abstract = {10.1073/pnas.0804758106 Accumulation of amyloid \^{I}²-peptide (A\^{I}²) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between A\^{I}² and the aldehyde-bearing cholesterol oxidation product 3-\^{I}²-hydroxy-5-oxo-5,6-cholestan-6-al is known to increase A\^{I}² amyloidogenicity. Here, we synthesized A\^{I}² variants site-specifically modified with the cholesterol aldehyde at Asp-1, Lys-16, or Lys-28, rather than studying mixtures. These distinct modifications have a similar effect on the thermodynamic propensity for aggregation, enabling aggregation at low concentrations. In contrast, the modification site differentially influences the aggregation kinetics; Lys-16-modified A\^{I}² formed amorphous aggregates fastest and at the lowest concentration (within 2 h at a concentration of 20 nM), followed by the Lys-28 and Asp-1 conjugates. Also, the aggregates resulting from A\^{I}² Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified A\^{I}² under identical conditions and at the same concentration. Our results show that A\^{I}² modification by cholesterol derivatives, especially at Lys-16, renders it kinetically and thermodynamically competent to form neurotoxic aggregates at concentrations approaching the physiologic concentration of A\^{I}².}, author = {Usui, Kenji and Hulleman, John D. and Paulsson, Johan F. and Siegel, Sarah J. and Powers, Evan T. and Kelly, Jeffery W.}, citeulike-article-id = {6074540}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0804758106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/44/18563.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/44/18563.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19841277}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19841277}, day = {3}, doi = {10.1073/pnas.0804758106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {aggregation, alzheimers\_disease, cholesterol, neurotoxicity, oxidation}, month = {November}, number = {44}, pages = {18563--18568}, posted-at = {2009-11-05 14:09:15}, priority = {0}, title = {Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity}, url = {http://dx.doi.org/10.1073/pnas.0804758106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:6074540 L3 - citeulike-article-id:6074540 N2 - 10.1073/pnas.0804758106 Accumulation of amyloid β-peptide (Aβ) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between Aβ and the aldehyde-bearing cholesterol oxidation product 3-β-hydroxy-5-oxo-5,6-cholestan-6-al is known to increase Aβ amyloidogenicity. Here, we synthesized Aβ variants site-specifically modified with the cholesterol aldehyde at Asp-1, Lys-16, or Lys-28, rather than studying mixtures. These distinct modifications have a similar effect on the thermodynamic propensity for aggregation, enabling aggregation at low concentrations. In contrast, the modification site differentially influences the aggregation kinetics; Lys-16-modified Aβ formed amorphous aggregates fastest and at the lowest concentration (within 2 h at a concentration of 20 nM), followed by the Lys-28 and Asp-1 conjugates. Also, the aggregates resulting from Aβ Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified Aβ under identical conditions and at the same concentration. Our results show that Aβ modification by cholesterol derivatives, especially at Lys-16, renders it kinetically and thermodynamically competent to form neurotoxic aggregates at concentrations approaching the physiologic concentration of Aβ. IS - 44 JF - Proceedings of the National Academy of Sciences EP - 18568 TI - Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity VL - 106 SP - 18563 KW - aggregation KW - alzheimers_disease KW - cholesterol KW - neurotoxicity KW - oxidation AU - Usui, Kenji AU - Hulleman, John AU - Paulsson, Johan AU - Siegel, Sarah AU - Powers, Evan AU - Kelly, Jeffery PY - 2009/11/03/ UR - http://dx.doi.org/10.1073/pnas.0804758106 ER -