2022 Winner: Investigating the Binding of Amyloid-beta with the Prion Protein Regulatory Domain

Project Information
Investigating the Binding of Amyloid-beta with the Prion Protein Regulatory Domain
Physical and Biological Sciences
Undergraduate Research in Science & Technology Grant
Alzheimer’s disease (AD), a neurodegenerative disease, is the most common form of dementia, which is responsible for more deaths than breast cancer and prostate cancer combined. The amyloid-beta peptide (Aβ) is the established causative agent of AD, but recent evidence supports that the cellular prion protein (PrPC) plays a key role in AD pathogenesis. Currently used medications for the treatment of AD only target Aβ, missing PrPC’s newly found role in the illness, thus limiting their effectiveness in terminating disease development and progression. Studies discovered that PrPC is an Aβ receptor because it increases the uptake of Aβ into neurons, accelerating the initial steps of AD development. The interface between Aβ and PrPC was identified by the Millhauser lab. My research aims to further investigate this interaction by determining the nature of the binding between Aβ and PrPC using two structural biological techniques. First, isothermal titration calorimetry (ITC) calculates the strength and mode of binding. Second, X-ray crystallography (XRC) provides data used to develop a high-resolution model of the protein-protein complex. My ITC and XRC experiments corroborate the fact that these proteins interact with each other with moderate affinity in a sequential binding mode with two sites. With the improved understanding of the dynamics and structure of the Aβ-PrPC complex, new therapeutics can be designed to hinder PrPC’s role as an Aβ receptor by interrupting this interaction, offering a more effective mechanism of treating AD.
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  • Irene Carolina Franco (Eight)