Year: 2009
Type: article
Abstract: Alzheimer's disease is the most common cause of dementia in elderly. In literature, this disease has been linked to the toxicity of beta-Amyloid peptide (Abeta). Abeta is generated from the Amyloid Precursor Protein (APP) by cleavage by both beta- and gamma-secretase. The gamma-secretase does not have a specific cleavage site and therefore produces Abeta peptides ranging from 33 to 49 amino acids length. The different peptide lengths show differences in predicted aggregation propensity by the TANGO algorithm. Recent data suggest that intermediates of the aggregation pathway are involved in the progression of Alzheimer's disease. Abeta40 comprises about 85% of the total Abeta produced. The rest of the pool includes approximately 10% Abeta42 and 5% other peptide lengths. Published data often only study the aggregation behaviour of Abeta40 and Abeta42. Information on the aggregation behaviour of other occurring Abeta lengths is scarce. Since these other lengths also occur in patient's brains, they cannot be ignored. Also, Alzheimer patients have a higher burden of longer Abeta lengths than healthy individuals. We investigate the behaviour of these other lengths in vitro. For this exploration, we use Thioflavin T Fluorescence (ThT) and Transmission Electron Microscopy. We found a fundamental difference in the aggregation kinetics and the morphology of the formed fibrils between different Abeta lengths. A higher TANGO score indicates a higher aggregation propensity. Abeta peptide length is more or less positively correlated with aggregating propensity according to TANGO. With ThT fluorescence, shorter and less amyloidogenic peptide lengths show longer nucleation phases combined with a fast fibril elongation. Whereas longer and more amyloidogenic peptides display very short nucleation phases and slower fibril growth. Electron microscopy showed that Abeta38 and Abeta40 form long, individual fibrils in which a regular twisting pattern is observed. Abeta42 and Abeta43 on the other hand, form shorter and thicker fibrils that are highly intertwined. Abeta46 does not form separate fibrils anymore but amorphous aggregates. We can conclude that high TANGO scores are correlated with the fast aggregation kinetics observed with ThT fluorescence. Increasing rates of aggregation seem to result in aggregates with different morphologies.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2142419825