UC San Diego

Neurodegenerative diseases have been a leading cause of disability and death worldwide. Pathologically, neurodegenerative diseases are associated with the abnormal accumulation of protein aggregates, also known as amyloids. This dissertation comprises three distinct yet interconnected studies focusing on the understanding, intervention, and detection of amyloid.

Chapter 2 elucidates the intricate relationships among surface hydrophobicity, β-sheet content, and proteolytic susceptibility in three amyloids: β-amyloid, prion, and α-synuclein. The findings reveal a negative correlation between surface hydrophobicity and β-sheet content across all three amyloids. Additionally, the correlation between susceptibility to enzymatic degradation by proteinase K and β-sheet content varies among these amyloids.

In Chapter 3, the focus shifts to the amyloidogenic peptide S192, a fragment from the SARS-CoV-2 spike protein, and its role in inducing the agglutination of red blood cells. A novel amyloid-binding molecule, BAM1-EG6, is identified as a promising candidate capable of binding to aggregated S192 and partially inhibiting its hemagglutination activity.

Chapter 4 presents a rapid, low-cost method for detecting amyloidogenic proteins in SDS-PAGE gels using amyloid-targeting fluorescent probes. This technique is capable of staining monomeric, oligomeric, and fibrillar forms of amyloids, and offers the advantage of staining amyloids against a background of human brain lysate in SDS-PAGE gels.

Collectively, these studies enhance our understating of the structural, functional and detection aspects of amyloids, and open new avenues for therapeutic strategies to address amyloid-associated conditions.