Department of ChemistryAlzheimer???s disease (AD) is the most common cause of dementia. The symptoms of AD mainly
include short-term memory loss, cognitive defects, and poor judgment, consequently leading to death.
Currently 28 million people worldwide are suffering from AD; however, a cure for the disease to
retard its initiation and progression has not been developed. Indeed, the discovery of the drug has
been very challenging due to the involvement of multiple pathogenic factors in the pathogenesis of AD.
For example, the aggregates of amyloidogenic amyloid-b (Ab) peptides are accumulated in the AD-affected
brain. Among the aggregates, soluble and structured Ab oligomers have been suggested to be
toxic to nerve cells. Additionally, highly concentrated metal ions [e.g., Cu(I/II), Zn(II), Fe(II/III)] are
found in senile plaques, composed of Ab aggregates. Disrupted homeostasis of these metal ions would
affect neuron signaling, apoptosis, and inflammation. Lastly, reactive oxygen species (ROS) can be
overproduced through Fenton-like reactions causing oxidative damage to nucleic acids and cellular
organelles. The studies presented in this thesis describe the development of chemical tools able to
regulate single or multiple pathogenic component(s). In Chapter 1, an introduction of the hypotheses
of AD is described, along with previously reported chemical tools designed to target pathological
elements. In Chapter 2, our interdisciplinary studies of new small molecules towards distinct
pathological factors, rationally designed via a novel structure-property-directed design strategy, are
summarized. Lastly, in Chapter 3, a series of fluorescent sensors for metal ions in living cells is
illustrated, which could provide a better understanding of a link of their concentration and
compartmentalization to the pathogenesis of AD. Overall, our approaches and findings presented
herein would be useful for constructing effective chemical tools and therapeutics for AD, ultimately
serving the illumination of complex pathogenesis of the disease in the future.ope
