CRYO-EM STRUCTURAL STUDIES OF AMYLOID FIBRILS FROM HUMAN NEURODEGENERATIVE DISEASES

Neurodegenerative diseases are conditions characterized by the death of neurons in the brain, leading to cognitive decline. Alzheimer's Disease is a common example of such a disease, which is often associated with the buildup of amyloid-containing aggregates in the brain. Tau protein and Amyloid-β-peptide (Aβ 40/42) are important proteins in the pathogenesis of neurodegenerative diseases, including AD, and have been studied using cryo-EM to better understand their role in the disease.

The research presented in this dissertation, which was funded by the NIH and supervised by Wen Jiang in collaboration with the Indiana University School of Medicine, focuses on structural studies of various amyloids in multiple neurodegenerative diseases. This thesis presents 38 cryo-EM structures of different types of amyloid filaments. Specifically, the research examines two prion protein amyloidoses: Prion-Protein cerebral amyloid angiopathy (PrP-CAA), caused by a nonsense mutation in the PRNP gene (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, caused by a missense mutation in the PRNP gene (F198S). The research also explores Multiple System Tauopathy with Presenile Dementia (MSTD), human trisomy 21, and two phenotypic variants of familial AD. The thesis also describes an on-grid affinity purification method for obtaining high-resolution cryo-EM structures of amyloid fibrils, such as Tau, Aβ 40/42, and TMEM106B, from the aforementioned diseases. Understanding the structure of these brain filaments has the potential to advance the development of superior animal and in vitro disease models, amyloid assembly inhibitors, and more precise imaging agents. Such progress may ultimately aid in comprehending the role of amyloid in the pathogenic mechanism of neurodegeneration and development of prevention and treatment strategies.