Understanding of Individual and Interconnected Actions of Pathological Features in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a fatal neurodegenerative disease which has symptoms related to memory loss and cognitive impairment. AD can be categorized as a protein misfolding disease, since abnormal accumulation and aggregation of amyloid-β (Aβ) peptides in the AD-affected brain are associated with neurotoxicity. Moreover, additional pathological features (e.g., metal ion dyshomeostasis, oxidative stress) also exist and are indicated to interact with Aβ leading to AD pathogenesis. For instance, upon binding of redox-active metal ions with Aβ, facilitation of Aβ aggregation, including generation of toxic oligomer species, and production of reactive oxygen species (ROS) are observed. The interconnections that affect various microenvironments in cellular systems, which in turn cause neuronal death, have hindered the identification of AD etiology. Therefore, the determination of an inter-relationship among multiple pathological factors in AD pathology would provide a better understanding of AD etiology. The work presented in this dissertation focuses on this goal. In Chapter 1, the assembly of Aβ and detailed characterization of Aβ oligomers, proposed to be primary toxic species, are introduced. The toxicity mechanisms of Aβ oligomers in cellular systems as well as effective inhibitors against Aβ aggregation, including oligomerization, are also presented. In Chapter 2, the investigations of the inter-relationship between multiple pathological features (e.g., Aβ, metals, metal-bound Aβ, ROS) and a neurotransmitter, dopamine, toward AD pathogenesis are described. The direct or indirect regulatory activities of dopamine against the pathological features via its oxidative transfigurations are observed, which provides advanced information on the role of the neurotransmitter in AD pathogenesis. Finally, in Chapter 3, our studies of fluorescent sensors for metal ions in living cells are reported. This work might be helpful to further probe metals' pathology in AD. Collectively, our work presented in this thesis illustrates a greater understanding and a better insightful view of AD pathology, which could be utilized for development of potential therapeutic agents for this disease.