UCLA

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases. Although AD is a disease of dementia and PD is predominantly a motor disease, both diseases are characterized by histological hallmarks formed from aggregates of amyloid-forming proteins. Amyloid plaques and neurofibrillary tangles, composed of amyloid-β and tau respectively, are the hallmarks of AD while Lewy bodies, composed of α-synuclein (α-syn), are the hallmarks of PD. Amyloid-forming proteins such as amyloid-β, tau, and α-syn are soluble and functional in their monomeric state. They can misfold and aggregate into fibrils, which themselves aggregate to form amyloid plaques, neurofibrillary tangles, and Lewy bodies. There is a tight correlation between neurofibrillary tangle formation and progression of AD, and between Lewy body formation and progression of PD, so it has long been hypothesized that amyloid fibrils are toxic and contribute to the pathogenesis of AD and PD. Supporting this hypothesis are studies demonstrating that existing amyloid fibrils can propagate or “seed” the formation of additional fibrils among cultured cells and in mice. Using the wealth of atomic resolution structures of amyloid fibrils determined by x-ray crystallography and cryo-electron microscopy, the Eisenberg group has designed peptides, antibodies, and small molecules that target tau and α-syn fibrils. In this dissertation research, I focus on characterizing three of these structure-based designs as potential diagnostics and therapeutics for AD and PD. First, I characterize magnetic nanoparticles functionalized with an α-syn-targeting peptide and determine that they can be used as an MRI contrast agent to distinguish mice with α-syn pathology from wild-type control mice. Second, I characterize a bivalent nanobody that can inhibit seeding by post-mortem brain extracts from AD patients and determine it can cross the blood-brain barrier in mice. Third, I characterize three small molecules that can disaggregate AD brain-extracted fibrils and determine that they can each reduce levels of aggregated tau in mice with tau pathology. Together, the studies in this dissertation demonstrate the potential of using structure-based design of diagnostics and therapeutics for diseases caused by the misfolding of amyloid-forming proteins.