UC Irvine

To understand and treat Alzheimer’s disease (AD), we need to understand the structures of the Aβ peptide aggregates that cause neurodegeneration. In this dissertation, I address this need by applying triangular trimers derived from Aβ to create antibodies for immunohistochemical studies and as vaccines against AD. Chapter 1 outlines the exponential growth of people who will live with AD and current therapies to alleviate symptoms or slow down the progression of AD. Here, Chapter 2 demonstrates the application of a conformationally defined Aβ-derived peptide (the 4AT-L trimer) to better understand the composition of Aβ pathology in people who lived with Late-Onset Alzheimer’s disease (LOAD). Chapter 3 expands on the subject of current peptide vaccines and immunotherapies against AD by discussing the composition of each therapy, the current state of clinical trials, and the possible future of these therapies. Chapter 4 demonstrates how a structurally defined Aβ antigen may be useful in treating AD-like symptoms in mice. Chapter 5 shows preliminary work demonstrating the recognition of pathology in people who lived with Down Syndrome and Alzheimer’s disease (DSAD). Lastly, Chapter 6 discusses the conclusions collected from the previous chapters and lists future directions that can be pursued by junior members of the Nowick Group.This body of work is one of the earliest collections of studies in the Nowick Group which provides a biological and therapeutic application to structurally defined triangular trimers derived from Aβ. Additional studies exploring the biological and therapeutic application of trimers of Aβ and associated antibodies will continue to address the need to understand the structures of the Aβ peptide aggregates that cause neurodegeneration. These efforts will contribute to a better understanding of neurodegeneration and develop therapies to slow down the progression of AD.