Abstract
Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncovalent and covalent interactions. Thus, Michael’s addition appears as a feasible type of interaction involving an α, β unsaturated carbonyl moiety to avoid pathological confirmation and further cytotoxicity. Moreover, we isolated three compounds from Antarctic lichens Cladonia cariosa and Himantormia lugubris: protolichesterinic acid (1), fumarprotocetraric acid (2), and lichesterinic acid (3). The maleimide cysteine labeling assay showed that compounds 1, 2, and 3 inhibit at 50 µM, but compounds 2 and 3 are statistically significant. Based on its inhibition capacity, we decided to test compound 2 further. Thus, our results suggest that compound 2 remodel soluble oligomers and diminish β sheet content, as demonstrated through ThT experiments. Hence, we added externally treated oligomers with compound 2 to demonstrate that they are harmless in cell culture. First, the morphology of cells in the presence of aggregates does not suffer evident changes compared to the control. Additionally, the externally added aggregates do not provoke a substantial LDH release compared to the control, indicating that treated oligomers do not provoke membrane damage in cell culture compared with aggregates alone. Thus, in the present work, we demonstrated that Michael’s acceptors found in lichens could serve as a scaffold to explore different mechanisms of action to turn tau aggregates into harmless species.
Highlights
Alzheimer’s disease (AD) is the most prevalent form of dementia [1], involving beta-amyloid (Aβ) and microtubule-associated protein tau
Tau protein participates in axonal transport and microtubule stability; several stressful factors can provoke it to detach from microtubules and form aggregates in soma and dendrites neuron cells [3]
Tau pathology involving the microtubule-binding domain (4R) is associated with PSP, CBD, AGD, CTE, and GGT; tau aggregates can be found in the medial temporal lobe, cortex, basal ganglia, subthalamic nucleus, and substantia nigra [4]
Summary
Alzheimer’s disease (AD) is the most prevalent form of dementia [1], involving beta-amyloid (Aβ) and microtubule-associated protein tau. As long the tau polymerization occurs, mature oligomers are formed whose content is a majority of β sheet content [6] These oligomers’ structures are detected at the prefrontal cortex in Braak stage I [7]. The amyloid hypothesis relies on the fact that Aβ accelerates the NFT formation and neuronal death in the neocortex [9] All these approaches focused on Aβ, including clinical trials, have failed since there are no cognitive improvements in patients with AD [10]. Considering that tau correlates better with cognitive impairment and dementia symptoms, drug discovery strategies focus on tau [12] Compounds such as cinnamaldehyde or anthraquinone can interact with tau by inhibiting cysteine interactions, promoting incompetent aggregate forms [13,14]. 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
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