Journal
CURRENT ALZHEIMER RESEARCH
Volume 9, Issue 8, Pages 962-971Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156720512803251129
Keywords
Alzheimer's; amyloid; membranes; non-fibrillar; pH
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Funding
- Spanish Ministry of Science and Innovation [FBU2007-64142]
- COST Action [TD1802]
- Grant Agency of Czech Academy of Sciences
- Czech national project COST [OC10053]
- [KAN 200520702]
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Granular non-fibrillar aggregates (GNAs) are identified as possible toxic species in Alzheimer's disease. GNAs form on the surface of negatively charged biological membranes and as a consequence of an acidic environment, off the polymerization pathway at neutral pH. A beta (1-40) GNAs disturb the bilayer structure of model membranes and seem to be more toxic to cells with negatively charged membranes (consequence of chronic pre-apoptosis). GNAs may be relevant in physiological situations associated to Alzheimer's disease: a local acidic pH at the cell surface (consequence of lipid oxidation or other cell insults) and acidification as a consequence of vascular events causing hypoxia. Together with previous descriptions of granular aggregates with poly-glutamine peptides related to Huntington's disease and the SH3 domain of PI3, GNAs related to Alzheimer's disease are a further example of a possible common aggregation and toxicity mechanism in conformational diseases. GNAs may represent a new pharmacological target in Alzheimer's disease.
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