Anthraquinone Derivative Reduces Tau Oligomer Progression by Inhibiting Cysteine‐Cysteine Interaction

Abstract

Tau protein is a natively unfolded protein whose primary role is to participate in axonal transport closely associated with microtubules. Neurodegenerative disorders including Alzheimer's disease and Tauopathies involved tau protein that is found hyperphosphorylated in vivo ; then, tau is detached from microtubules to form toxic aggregates or oligomers, which have a deleterious effect on membranes, triggering an inflammatory response. Considering finding tau inhibitors, we isolated two compounds in the ethyl acetate extract from Xanthoria ectaneoides (Nyl.) Zahlbr; ergosterol peroxide ( 1 ) and a new anthraquinone ( 2 ). We established the structure through spectroscopic data and biogenic considerations, and we named it “2‐hydroxy‐3‐((8‐hydroxy‐3‐methoxy‐6‐methylanthraquinonyl)oxy)propanoic acid”. This new anthraquinone was evaluated as a tau inhibitor by ThT fluorescence, dot blot assays and total internal reflection fluorescence microscopy. Our results strongly suggest that this anthraquinone remodels soluble oligomers and diminishes β‐sheet content. Moreover, through the fluorescence labeling of cysteine inside of the microtubule‐binding domain (4R), we showed that this anthraquinone could reduce the oligomers progression by inhibiting cysteine interactions.

Hyperphosphorylated tau aggregation and cytotoxicity modulators screen identified prescription drugs linked to Alzheimer's disease and cognitive functions

“…One of such compounds, methylene blue, advanced to clinical trials but failed 48 . Many other tau aggregation inhibitors (TAIs) were later found to be non-selective redox modulators 49 , due apparently to the susceptibility of unmodified tau aggregation to the redox state of the two cysteine residues of tau protein 50 – 52 . Heparin-induced tau aggregates had a different proteinase K digestion pattern from its hyperphosphorylated counterpart from the brain 53 .…”

The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells

“…The excess of the fluorophore was eluted as described before. The induction of the aggregation of the protein labeled was done as described [ 14 , 25 ]. Briefly, tau protein was induced by adding a molar excess of heparin (10:40 µM) for 4 h. After that, samples were read in a Biotek H1 multimode reader in a 96-black plate flat bottom.…”

“…Thus, considering that tau correlates better with cognitive impairment and dementia symptoms, drug discovery strategies focus on tau [ 12 ]. Moreover, compounds such as cinnamaldehyde or anthraquinone can interact with tau by inhibiting cysteine interactions, promoting incompetent aggregate forms [ 13 , 14 ]. Here, we present the activities of three lichen compounds capable of inhibiting tau aggregation, and the aggregates treated with compound 2 can prevent cell membrane damage and further LDH leaking.…”

The Cytotoxic Effect of α‐Synuclein Aggregates

“…α‐synuclein samples at 30 μM were incubated at 37° C under constant shaking at 300 rpm for 48 h to form aggregates, after that added 25 μM solution of ThT and incubated for one h at room temperature before fluorescence reading with an excitation wavelength at 440 nm and emission wavelength at 485 nm in a 96 well plate as described [27] …”