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

Abstract

A catecholamine neurotransmitter, dopamine (DA), is suggested to be linked to the pathology of dementia; however, the involvement of DA 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 DA and its rationally designed structural derivatives (1-6) based on DA'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 DA 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, DA and the derivatives (i.e., 3 and 4) 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, DA 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 DA 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.

Inhibition of Colony-Stimulating Factor 1 Receptor by PLX3397 Prevents Amyloid Beta Pathology and Rescues Dopaminergic Signaling in Aging 5xFAD Mice

“…Several lines of investigation have shown that dopamine increases cortical excitability by acting through D2-like receptors; these observations support the idea that disruption of the DA system is associated with AD pathophysiology. Currently, dysfunction of DA transmission has been hypothesized as a new player in AD pathophysiology [29]. Consistent with a previous study showing DA neuron loss in the midbrain of 5xFAD mice [25], our study showed that the D2R levels in the striatum of 5xFAD mice were significantly lower than those in the striatum of WT mice.…”

Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

“…[67] Redox cycling induced by DA on the copper-peptide complexes produces several modifications by DA-derived species of both Ab and PrP peptides,a sw ell as O-atom insertion at His and Met residues. [74,76,78,83] Interestingly,b inding of the peptides to membranes has aq uenching effect on Cu 2+ -promoted DA oxidation, with the exception of Ab,for which the inhibition is only partial. [78] Thequenching effect of the membrane is due to the trapping of Cu + in the sites of the peptides containing asequence with two close methionines, 1 MXXXM 5 -atthe Nterminal of aSyn, and -109 MXHM 112 -inthe fragment following the polar region comprising the octarepeats of PrP peptides.…”

“…In the case of αSyn ( K D ≈0.20 μ m ), we found that it decreases Cu 2+ reactivity, but these experiments should be repeated using oligomers instead of monomeric αSyn, in view of the strong promotion of ROS production of αSyn aggregates in the presence of Cu 2+ . Redox cycling induced by DA on the copper–peptide complexes produces several modifications by DA‐derived species of both Aβ and PrP peptides, as well as O‐atom insertion at His and Met residues . Interestingly, binding of the peptides to membranes has a quenching effect on Cu 2+ ‐promoted DA oxidation, with the exception of Aβ, for which the inhibition is only partial .…”

Dopamin, oxidativer Stress und Protein‐Chinonmodifikationen bei Parkinson und anderen neurodegenerativen Erkrankungen

“…[74][75][76] Für aSyn (K D % 0.20 mm) [82] fanden wir eine Abnahme der Cu 2+ -Reaktivität, [77] doch sollten diese Experimente mit Oligomeren anstelle von Monomeren von aSyn wiederholt werden, weil aSyn-Aggragate die ROS-Bildung in Gegenwart von Cu 2+ stark begünstigen. [74,76,78,83] Die Bindung der Peptide an Membranen dämpft die Cu 2+ -induzierte DA-Oxidation mit Ausnahme von Ab,b ei dem nur eine partielle Hemmung auftritt. [74,76,78,83] Die Bindung der Peptide an Membranen dämpft die Cu 2+ -induzierte DA-Oxidation mit Ausnahme von Ab,b ei dem nur eine partielle Hemmung auftritt.…”

“…[67] Die Redoxzyklen, die durch DA an den Kupfer-Peptidkomplexen induziert werden, verursachen verschiedene Modifikationen an den Ab-u nd PrP-Peptiden durch Verbindungen, die sich von DA ableiten, außerdem einen O-Atom-Einschub an His-und Met-Resten. [74,76,78,83] Die Bindung der Peptide an Membranen dämpft die Cu 2+ -induzierte DA-Oxidation mit Ausnahme von Ab,b ei dem nur eine partielle Hemmung auftritt. [78] [51,84] Das wichtigste eisenhaltige Protein im Gehirn ist Ferritin (ein aus vielen Untereinheiten bestehendes Eisenspeicherprotein mit H-und L-Ketten), das in besonders großen Mengen in Gliazellen und in geringeren Mengen in dopaminergen Neuronen vorkommt.…”