Towards Developing Chemical Imaging Tools to Investigate the Molecular Etiology of Cerebral Amyloid Angiopathy and Alzheimer's Disease

Amyloid fibrils are protein aggregates that are commonly associated with many diseases, such as Alzheimer's Disease (AD). A common comorbidity of AD is cerebral amyloid angiopathy (CAA). In CAA, Aβ fibrils contribute to the weakening of blood vessel walls, leading to hemorrhages that accelerates neurodegeneration. However, a direct link between how different amyloid fibril structures (polymorphs) and CAA has not yet been established. We are developing characterization methods using Raman microscopy to quantitatively assess the molecular-level structural differences of fibrils directly in brain parenchyma and blood vessels. For example, we recently developed methods to measure important dihedral and bond orientation angles in fibrils. To determine the molecular-level structure of different polymorphs, we use these angular measurements as experimental constraints in molecular dynamics simulations. The resulting simulations from the production runs yield an ensemble of structures that are consistent with the experimental Raman data. We are working towards translating some of our methodologies towards Raman imaging applications to quantitively assess amyloid fibril structures found in plaques from brain tissue of AD and CAA patients. Our results show that brain-derived Aβ fibrils have different vibrational signatures compared to those formed in vitro. We also observe structural differences between fibrils found in vascular plaques compared to parenchymal plaques in AD patients. In addition, fibrils found in parenchymal plaques have consistent structural signatures in different regions of the brain, whereas fibrils found in vascular plaques show different structures depending on the region of the brain they are found. These findings emphasize the importance of studying physiologically relevant fibril polymorphs, which could advance our understanding of the molecular mechanisms underlying CAA and inform the development of therapeutic strategies.