Abstract
Amyloid β (Aβ) peptide aggregation is the main molecular mechanism underlying the development of Alzheimer's disease, the most widespread form of senile dementia worldwide. Increasing evidence suggests that the key factor leading to impaired neuronal function is accumulation of water-soluble Aβ oligomers rather than formation of the senile plaques created by the deposition of large fibrillary aggregates of Aβ. However, several questions remain about the preliminary steps and the progression of Aβ oligomerization.
We show that the initial stages of the aggregation of fluorescently labeled Aβ can be determined with a high degree of precision and at physiological (i.e., nanomolar) concentrations by using either steady-state fluorimetry or time-correlated single-photon counting.
We study the dependence of the oligomerization extent and rate on the Aβ concentration. We determine the chemical binding affinity of fluorescently labeled Aβ for liposomes that have been recently shown to be pharmacologically active in vivo, reducing the Aβ burden within the brain. We also probe their capacity to hinder the Aβ oligomerization process in vitro.
We introduced a fluorescence assay allowing investigation of the earliest steps of Aβ oligomerization, the peptide involved in Alzheimer's disease. The assay proved to be sensitive even at Aβ concentrations as low as those physiologically observed in the cerebrospinal fluid.
This work represents an extensive and quantitative study on the initial events of Aβ oligomerization at physiological concentration. It may enhance our comprehension of the molecular mechanisms leading to Alzheimer's disease, thus paving the way to novel therapeutic strategies.
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•We determined the initial stages of Aβ aggregation by fluorimetry.•We study the dependence of oligomerization rate on the Aβ concentration.•We determine the binding of Aβ to liposomes reducing the Aβ burden in the brain.•We probe the liposomes' capacity to hinder the Aβ oligomerization process.