One Plaque at a Time: Investigating Heterogeneities of Amyloid Aggregates and Their Correlation with Alzheimer's Disease Progression

Abstract

Electronic Thesis or DissertationAlzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the accumulation of amyloid beta (Aβ) protein into fibrillar aggregates, known as plaques, within the brain. However, the underlying mechanisms of aggregate formation, their evolution throughout disease progression, and their relationship to AD severity remain largely unknown. To address these gaps in knowledge, we employ infrared (IR) imaging, an analytical technique combining IR spectroscopy with optical microscopy, to investigate the structural heterogeneities of Aβ plaques in human brain tissues. Using this method, significant variations in plaque secondary structural composition are revealed. Amyloid plaques are usually characterized using histological staining. A well-known morphological type, the dense core plaque, has historically been thought to be composed of mature Aβ fibrils. Previous studies have shown that mature Aβ fibrils exhibit a parallel β-sheet secondary structure, while Aβ oligomers may have a differing secondary structure, such as antiparallel β-sheet. Therefore, it has been understood that the fibrillar cores of these plaques are exclusively composed of parallel β-sheets. However, we demonstrate that these cores exhibit a variety of secondary structural conformations, including both parallel and antiparallel β-sheets, and differ in localized β-sheet contribution. These findings suggest that a heterogeneous mixture of Aβ fibrils with varying secondary structures exists within plaques, rather than a singular, distinct conformation. Furthermore, the secondary structure distribution of different Aβ aggregates evolves with disease progression, and we show that specifically the β-sheet content in plaques increases as AD progresses. These results highlight and reemphasize the role of fibrillar aggregates in AD pathology and also point to the possibility of categorizing plaques based on their chemistry, which can pave the way for the development of effective targeted treatment options for AD