Tools of the Trade: Investigations into Design Strategies of Small Molecules to Target Components in Alzheimer's Disease

Abstract

The growing prevalence of Alzheimer's disease (AD) has warranted the development of effective therapeutic methods. Current available drugs for AD (i.e., acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists) have only offered brief symptomatic relief. Considering that the numbers affected by AD are projected to substantially rise, long-term strategies are urgently needed. The multiple series of small molecules to combat AD have been expanded, with current methods taking aim at factors, such as misfolded protein accumulation, metal ion dyshomeostasis, and oxidative stress. This concept article focuses on describing the design of compounds to target various components of AD and underlining recent advances that have been made.

A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms

“…1–4 As such, fatalities resulting from this deadly malady have continued to increase to the point where today almost one-third of every senior citizen will be affected by AD or a related form of dementia. 5 The costs associated with providing the long-term care and resources required by those suffering from AD have also reached staggering levels.…”

“…For example, in vitro analyses often require the experimentalist to narrow the scope of their study to a few potential players (e.g., misfolded proteins) and often deviate from physiological relevancy. 1–4 Similarly, in vivo studies are limited by the absence of accurate models that fully mimic human AD. 6 Due to these inherent complexities along with the impossibility of addressing every potential factor contributing toward neuronal death in a single report, we have chosen to focus our investigation on the amyloid-β (Aβ) peptide, a hallmark of the disease which is known to aggregate to form characteristic senile plaques, and its interplay with metal ions [e.g., Cu(II), Zn(II)].…”

“…1–4,7–14 Metal ions were incorporated into our studies because of their extensively explored involvement in the facilitation of Aβ aggregation pathways and generation of reactive oxygen species (ROS) via Fenton-like reactions in vitro. 2–4,7–14 It is important, however, that we specify that by focusing our analysis on the aggregation and interaction of Aβ and metal ions, we are not implying that these are the sole causes of the disorder.…”

“…1–4,7–14 For example, Aβ oligomer load has been closely correlated with cognitive impairment and behavioral tests in transgenic AD mouse models. 1,3 Furthermore, multiple cell and transgenic mouse studies have clearly identified Aβ as a contributor to the diminished mitochondrial function observed in AD.…”

“…In order to advance our understanding of these pathways, the use of chemical tools, capable of elucidating the mechanisms of these processes at the molecular level, will be of indispensable value. 2,4,14–22 …”