Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity
- 3 November 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 106 (44), 18563-18568
- https://doi.org/10.1073/pnas.0804758106
Abstract
Accumulation of amyloid beta-peptide (A beta) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between A beta and the aldehyde-bearing cholesterol oxidation product 3-beta-hydroxy-5-oxo-5,6-secocholestan-6-al is known to increase A beta amyloidogenicity. Here, we synthesized A beta 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 beta 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 beta Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified A beta under identical conditions and at the same concentration. Our results show that A beta 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 beta.Keywords
This publication has 42 references indexed in Scilit:
- Experimental Constraints on Quaternary Structure in Alzheimer's β-Amyloid FibrilsBiochemistry, 2005
- Conformational stability of amyloid fibrils of β2‐microglobulin probed by guanidine‐hydrochloride‐induced unfoldingFEBS Letters, 2004
- Transthyretin Aggregation under Partially Denaturing Conditions Is a Downhill PolymerizationBiochemistry, 2004
- Small assemblies of unmodified amyloid β-protein are the proximate neurotoxin in Alzheimer’s diseaseNeurobiology of Aging, 2004
- Metabolite-initiated protein misfolding may trigger Alzheimer's diseaseProceedings of the National Academy of Sciences, 2004
- Evidence for Ozone Formation in Human Atherosclerotic ArteriesScience, 2003
- Alzheimer Disease in the US PopulationArchives of Neurology, 2003
- Chemistry and Biochemistry of Oxidative Stress in Neurodegenerative DiseaseCurrent Medicinal Chemistry, 2001
- Amyloid β protein 1–40 and 1–42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer diseaseNeuroscience Letters, 2001
- Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicityEuropean Journal of Biochemistry, 2000