Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid‑β Aggregation, Oxidative Stress, and Inflammation in Alzheimer’s Disease

A catecholamine neurotransmitter, dopamine (<b>DA</b>), is suggested to be linked to the pathology of dementia; however, the involvement of <b>DA</b> and its structural analogues in the pathogenesis of Alzheimer’s disease (AD), the most common form of dementia, composed of multiple pathogenic factors has not been clear. Herein, we report that <b>DA</b> and its rationally designed structural derivatives (<b>1</b>–<b>6</b>) based on <b>DA</b>’s oxidative transformation are able to modulate multiple pathological elements found in AD [i.e., metal ions, metal-free amyloid-β (Aβ), metal-bound Aβ (metal–Aβ), and reactive oxygen species (ROS)], with demonstration of detailed molecular-level mechanisms. Our multidisciplinary studies validate that the protective effects of <b>DA</b> and its derivatives on Aβ aggregation and Aβ-mediated toxicity are induced by their oxidative transformation with concomitant ROS generation under aerobic conditions. In particular, <b>DA</b> and the derivatives (i.e., <b>3</b> and <b>4</b>) show their noticeable anti-amyloidogenic ability toward metal-free Aβ and/or metal–Aβ, verified to occur via their oxidative transformation that facilitates Aβ oxidation. Moreover, in primary pan-microglial marker (CD11b)-positive cells, the major producers of inflammatory mediators in the brain, <b>DA</b> and its derivatives significantly diminish inflammation and oxidative stress triggered by lipopolysaccharides and Aβ through the reduced induction of inflammatory mediators as well as upregulated expression of heme oxygenase-1, the enzyme responsible for production of antioxidants. Collectively, we illuminate how <b>DA</b> and its derivatives could prevent multiple pathological features found in AD. The overall studies could advance our understanding regarding distinct roles of neurotransmitters in AD and identify key interactions for alleviation of AD pathology

Tuning Structures and Properties for Developing Novel Chemical Tools toward Distinct Pathogenic Elements in Alzheimer’s Disease

Multiple pathogenic factors [e.g., amyloid-β (Aβ), metal ions, metal-bound Aβ (metal–Aβ), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer’s disease (AD). In order to elucidate the roles of pathological elements in AD, chemical tools able to regulate their activities would be valuable. Due to the complicated link among multiple pathological factors, however, it has been challenging to invent such chemical tools. Herein, we report novel small molecules as chemical tools toward modulation of single or multiple target(s), designed via a rational structure-property-directed strategy. The chemical properties (e.g., oxidation potentials) of our molecules and their coverage of reactivities toward the pathological targets were successfully differentiated through a minor structural variation [i.e., replacement of one nitrogen (N) or sulfur (S) donor atom in the framework]. Among our compounds (<b>1</b>–<b>3</b>), <b>1</b> with the lowest oxidation potential is able to noticeably modify the aggregation of both metal-free Aβ and metal–Aβ, as well as scavenge free radicals. Compound <b>2</b> with the moderate oxidation potential significantly alters the aggregation of Cu­(II)–Aβ₄₂. The hardly oxidizable compound, <b>3</b>, relative to <b>1</b> and <b>2</b>, indicates no noticeable interactions with all pathogenic factors, including metal-free Aβ, metal–Aβ, and free radicals. Overall, our studies demonstrate that the design of small molecules as chemical tools able to control distinct pathological components could be achieved via fine-tuning of structures and properties

Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid‑β Peptides

An amyloidogenic peptide, amyloid-β (Aβ), has been implicated as a contributor to the neurotoxicity of Alzheimer’s disease (AD) that continues to present a major socioeconomic burden for our society. Recently, the use of metal complexes capable of cleaving peptides has arisen as an efficient tactic for amyloid management; unfortunately, little has been reported to pursue this strategy. Herein, we report a novel approach to validate the hydrolytic cleavage of divalent metal complexes toward two major isoforms of Aβ (Aβ₄₀ and Aβ₄₂) and tune their proteolytic activity based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which could be correlated to their anti-amyloidogenic properties. Such metal-dependent tunability was facilitated employing a tetra-<i>N</i>-methylated cyclam (TMC) ligand that imparts unique geometric and stereochemical control, which has not been available in previous systems. Co­(II)­(TMC) was identified to noticeably cleave Aβ peptides and control their aggregation, reporting the first Co­(II) complex for such reactivities to the best of our knowledge. Through detailed mechanistic investigations by biochemical, spectroscopic, mass spectrometric, and computational studies, the critical importance of the coordination environment and acidity of the aqua-bound complexes in promoting amide hydrolysis was verified. The biological applicability of Co­(II)­(TMC) was also illustrated via its potential blood-brain barrier permeability, relatively low cytotoxicity, regulatory capability against toxicity induced by both Aβ₄₀ and Aβ₄₂ in living cells, proteolytic activity with Aβ peptides under biologically relevant conditions, and inertness toward cleavage of structured proteins. Overall, our approaches and findings on reactivities of divalent metal complexes toward Aβ, along with the mechanistic insights, demonstrate the feasibility of utilizing such metal complexes for amyloid control