Mechanistic Insight into the Design of Chemical Tools to Control Multiple Pathogenic Features in Alzheimer’s Disease

Alzheimer's disease (AD) is the most common form of dementia and is characterized by memory loss and cognitive decline. Approximately 50 million people worldwide are suffering from AD and related dementias. Very recently, the first new drug targeting amyloid-β (Aβ) aggregates has been approved by the United States Food and Drug Administration, but its efficacy against AD is still debatable. Other available treatments temporarily relieve the symptoms of AD. The difficulty in discovering effective therapeutics for AD originates from its complicated nature, which results from the interrelated pathogenic pathways led by multiple factors. Therefore, to develop potent disease-modifying drugs, multiple pathological features found in AD should be fully elucidated.Our laboratory has been designing small molecules as chemical tools to investigate the individual and interrelated pathologies triggered by four pathogenic elements found in the AD-affected brain: metal-free Aβ, metal-bound Aβ, reactive oxygen species (ROS), and acetylcholinesterase (AChE). Aβ peptides are partially folded and aggregate into oligomers, protofibrils, and fibrils. Aβ aggregates are considered to be neurotoxic, causing membrane disruption, aberrant cellular signaling, and organelle dysfunction. In addition, highly concentrated metal ions accumulate in senile plaques mainly composed of Aβ aggregates, which indicates that metal ions can directly interact with Aβ. Metal binding to Aβ affects the aggregation and conformation of the peptide. Moreover, the impaired homeostasis of redox-active Fe(II/III) and Cu(I/II) induces the overproduction of ROS through Fenton chemistry and Fenton-like reactions, respectively. Dysregulated ROS prompt oxidative-stress-damaging biological components such as lipids, proteins, and nucleic acids and, consequently, lead to neuronal death. Finally, the loss of cholinergic transmission mediated by the neurotransmitter acetylcholine (ACh) contributes to cognitive deficits observed in AD.In this Account, we illustrate the design principles for small-molecule-based chemical tools with reactivities against metal-free Aβ, metal-bound Aβ, ROS, and AChE. More importantly, mechanistic details at the molecular level are highlighted with some examples of chemical tools that were developed by our group. The aggregation of metal-free Aβ can be modulated by modifying amino acid residues responsible for self-assembling Aβ or disassembling preformed fibrils. To alter the aggregation and cytotoxicity profiles of metal-bound Aβ, ternary complexation, metal chelation, and modifications onto metal-binding residues can be effective tactics. The presence and production of ROS are able to be controlled by small molecules with antioxidant and metal-binding properties. Finally, inhibiting substrate access or substrate binding at the active site of AChE can diminish its activity, which restores the levels of ACh. Overall, our rational approaches demonstrate the feasibility of developing small molecules as chemical tools that can target and modulate multiple pathological factors associated with AD and can be useful for gaining a greater understanding of the multifaceted pathology of the disease.