UC San Diego

Alzheimer’s disease (AD) is the most common type of dementia affecting more than 44 million patients in worldwide. AD accounts for 60 to 80 percent of dementia cases. AD is characterized by the progressive loss of memory and cognition. The pathological hallmark of AD is the deposition of fibrillar amyloid plaques in the brains of AD patients. Amyloid beta (Aβ) proteins, the major constituents of these plaques, are derived by enzymatic cleavage from the transmembrane amyloid precursor protein (APP). Although accumulation of Aβ plaques in AD brains was believed to be directly correlated to the disease, increasing evidence indicates that small Aβ oligomers are the main toxic species. However, the exact disease mechanism has not yet been fully elucidated. A prevailing mechanism of AD pathology postulates that Aβ oligomers negatively affect neuronal function and survival by forming ion permeable pores, resulting in the destabilization of cell ionic homeostasis. This dissertation investigates the structures and ion conducting properties of Aβ oligomers in lipid membranes as well as develops new technique that can be applied to elucidate the mechanism of unknown disease pathologies. In chapter 2, I present the biophysical characterizations of two most abundant Aβ proteins (Aβ1-42 and AβpE3-42) in lipid membranes using AFM and Black Lipid Membrane (BLM) techniques to give insight toward finding the disease mechanisms. In chapter 3, I show the structures and ion conducting properties of Aβ1-42 and Aβ17-42 (or p3) in membranes comprised of natural brain total lipid extract and compare the results from other model lipid membranes. In chapter 4, I show the effect of an AD therapeutic candidate molecule on Aβ structures and ion conducting activities. In chapter 5, I show the development of new technique called Nanofiber optical force transducer. This new technique can measure sub pN force from living organisms. This multiscale study of structure-function relationship in Aβ proteins provides insight into AD mechanism and specific targets for the development of therapeutic strategies for the treatment AD.