Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is one of the most devastating forms of dementia, without reliable treatments to cure, delay the onset, or prevent the disease progression. The proposed toxic mechanisms of AD include amyloidogenesis of amyloid β (Aβ), metal ion dyshomeostasis, redox active metal−Aβ inclusion complex formation, and generation of excessive reactive oxygen and nitrogen species (ROS and RNS). The imbalance in redox homeostasis causes oxidative stress, DNA damage, mitochondrial dysfunction, and inflammation, which collectively become a major hurdle in the development of effective therapeutic agents for multifactorial AD. This necessitates a multifunctional strategy to develop effective therapeutic agents to inhibit multifaceted toxicity. In this context, we report a rational design, synthesis, and detailed study to identify a small molecule multifunctional modulator (MFM) inspired by the human origin tripeptide. The lead, MFM 4, chelates and sequesters metal ions, disrupts their redox cycles, prevents excessive ROS production and oxidative stress, ameliorates oxidative DNA damage and mitochondrial dysfunction, and modulates Nrf2 protein signaling under oxidative stress conditions by eliminating the toxic stress elements. The MFM 4 was found to inhibit metal-dependent and -independent Aβ aggregation and qualified as a suitable candidate to inhibit Aβ-induced neuronal toxicity. The NMR spectroscopy study revealed molecular-level interactions of 4 with Aβ42, which explain the mechanism of aggregation inhibition. Furthermore, 4 effectively inhibited inflammation as revealed by reduction in nitric oxide (NO) production in LPS-activated glial cells. These key features make 4 a potential MFM platform to develop therapeutic agents for metal (Cu, Zn and Fe)-dependent and -independent multifaceted Aβ toxicity of AD.

Intranasal administration of dauricine loaded on graphene oxide: multi-target therapy for Alzheimer's disease

“…Recent years, there are many natural product derived small molecules and polymer based multi-target therapeutic strategies (Rajasekhar et al, , 2020Samanta et al, 2019;Datta et al, 2020). As one of the main pathogenic mechanisms of AD, Ab amyloid precipitation has always been the focus of AD treatment research (Rajasekhar et al, 2015;Rojo et al, 2017;.…”

Role of Post‐translational Modifications in Alzheimer's Disease

“…The multifaceted toxicity of AD mediated through protein aggregation induces neurodegeneration, oxidative stress, neuroinflammation, biomolecule and mitochondrial damage, synaptic damage and cell death. Multifunctional inhibitors are developed to address this multifaceted toxicity and show good potential in preclinical studies, although in vivo efficacies are yet to be assessed –. In essence, revisiting the current approach of drug development is essential to target the multifaceted toxicity of AD.…”

Naphthalene monoimide derivative ameliorates amyloid burden and cognitive decline in a transgenic mouse model of Alzheimer’s disease

“…1G). 1 H NMR spectra of TGR63 (1 mM) were acquired in the absence and presence of Aβ42 (10 µM) at different incubation time points (24, 48 and 72 h) using WATERGATE sequence for solvent suppression in PBS buffer (10 mM, pH= 7.4) containing D2O (12%) (20). TGR63 alone showed aromatic protons of NMI core and aniline moiety (a-f) in the chemical shift range of 6.5-8.8 ppm (Fig.…”

“…These facts and reports have underscored the importance of clearing or reducing the Aβ burden from the brain as a primary target to develop therapeutic agents for the treatment of AD (17)(18)(19). The amyloid toxicity emphasizes the need for a novel drug design strategy to ameliorate Aβ burden-associated plasma membrane toxicity, cognitive decline and memory (STM and LTP) impairment under progressive AD pathogenesis (20)(21)(22). We designed and synthesized a set of novel small molecules (TGR60-…”