Alzheimer’s Disease (AD) impacts over 5.7 billion people in the U.S. each year, costing over $225 billion in patient care. AD is characterized by the presence of neurofibrillary tangles (NFTs) and senile plaques (SPs) from increased concentrations of amyloid-β-peptide (Aβ) are comprised of monomers, soluble oligomers, and insoluble fibrils that lead to plaque formation. Many experimental studies suggest that smaller oligomeric forms of soluble Ab are neurotoxic than larger amyloid aggregates. Thus far, in vitro studies of Aβ dimers, trimers, and tetramers permeate and disrupt membranes, cause sporadic cytosolic calcium signaling in both astrocytes and neurons, and cause neuroinflammation. Furthermore, only toxic low molecular weight oligomers (LMWO) Aβ dimers have been isolated, while no one has purified trimers and tetramers from brain tissue. High molecular weight oligomers (HMWO) tetramers, dodecamers, or higher prepared in vitro also show toxicity and increased binding to synaptic sites. However, the method used to prepare HMWO results in a heterogeneous mixture of Aβ oligomers and not a single oligomeric entity making it challenging to identify neurotoxic species. Therefore, there is a critical need for a process that results in stable individual Aβ oligomers for identifying the neurotoxic molecular target. Here we will present a strategy for studying Aβ aggregation under physiological conditions so that we can quantify the variety of species that form. We will present studies from fluorescence, atomic force microscopy, dynamic light scattering, and transmission electron microscopy showing that pH has a significant effect on the size and number size of species formed as well as the kinetics of aggregation. These studies will allow us to identify conditions and time points where we can identify and produce Aβ oligomers that can be used to identify which species are most neurotoxic.

Studying beta amyloid oligomer formation using flourescence anisotropy and atomic force microscopy

2019 Spring National Meeting

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