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. 2019 Mar 26;13:249. doi: 10.3389/fnins.2019.00249

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Copyright © 2019 Chalatsa, Arvanitis, Koulakiotis, Giagini, Skaltsounis, Papadopoulou-Daifoti, Tsarbopoulos and Sanoudou.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Summary diagram of the trans-crocin 4 and trans-crocetin effects on APP processing, and tau phosphorylation. (A) APP is processed by the non-amyloidogenic (alpha) or the amyloidogenic (beta) proteolytic pathways. Through the non-amyloidogenic pathway, APP is cleaved by the alpha secretases to produce soluble APP alpha (sAPPα) and APP-C83 in the plasma membrane. APP-C83 is cleaved by the gamma secretases (PSEN1 and PSEN2) to produce APP intracellular C-terminal domain (AICD) and P3 peptides. Through the amyloidogenic pathway, APP is cleaved by BACE1 (beta secretase) releasing sAPPβ to the extracellular space, and leaving APP-C99 in the plasma membrane. APP-C99 is subsequently processed by the gamma secretases into amyloid beta (Aβ) and AICD. Some species of Aβ, in particular Aβ_1-42, Aβ_1-40, and Aβ_3-40, are particularly toxic forming protofibrils, annular assemblies, soluble toxic oligomers, and insoluble inert β-sheet amyloid fibers extracellularly. The accumulation of these fibers ultimately lead to synaptic failure, neuronal death and AD. Trans-crocin 4 and trans-crocetin block the amyloidogenic pathway in the SH-SY5Y-APP AD model by reducing the levels of BACE1 and gamma secretases. In addition, trans-crocin 4 reduces the levels of APP-C99. (B) Tau (shown as multiple black square units) is a microtubule (MT, shown as dark and light gray circles) associated protein enhancing their stabilization (left panel). Tau protein is phosphorylated at multiple sites by GSK3β and ERK1/2 kinases. Hyperphosphorylation of tau (shown as multiple black square units with black circles at their ends when phosphorylated) leads to its dissociation from microtubules, microtubule destabilization, loss of dendritic microtubules and synapses, interruption of axonal transport, plasma membrane degeneration, neuronal loss and AD development (middle panel). The hyperphosphorylated and misfolded tau forms intracellular fibrils and neurofibrillary tangles (NFTs) (right panel). Trans-crocin 4 and trans-crocetin block the formation of NFTs in the PC12-htau AD model by reducing the tau phosphorylation at multiple sites as well as the activities and levels of tau kinases.