Organophosphorus compounds (OPs) involving life-threatening nerve agents (NA) have been known for several decades. Despite a clear mechanism of their lethality caused by the irreversible inhibition of acetylcholinesterase (AChE) and manifested via overstimulation of peripheral nicotinic and muscarinic acetylcholine (ACh) receptors, the mechanism for central neurotoxicity responsible for acute or delayed symptoms of the poisoning has not been thoroughly uncovered. One of the reasons is the lack of a suitable model. In our study, we have chosen the SH-SY5Y model in both the differentiated and undifferentiated state to study the effects of NAs (GB, VX and A234). The activity of expressed AChE in cell lysate assessed by Ellman's method showed 7.3-times higher activity in differentiated SH-SY5Y cells in contrast to undifferentiated cells, and with no involvement of BuChE as proved by ethopropazine (20 µM). The activity of AChE was found to be, in comparison to untreated cells, 16-, 9.3-, and 1.9-times lower upon A234, VX, and GB (100 µM) administration respectively. The cytotoxic effect of given OPs expressed as the IC50 values for differentiated and undifferentiated SH-SY5Y, respectively, was found 12 mM and 5.7 mM (A234), 4.8 mM and 1.1 mM (VX) and 2.6 mM and 3.8 mM (GB). In summary, although our results confirm higher AChE expression in the differentiated SH-SY5Y cell model, the such higher expression does not lead to a more pronounced NA cytotoxic effect. On the contrary, higher expression of AChE may attenuate NA-induced cytotoxicity by scavenging the NA. Such finding highlights a protective role for cholinesterases by scavenging Novichoks (A-agents). Second, we confirmed the mechanism of cytotoxicity of NAs, including A-agents, can be ascribed rather to the non-specific effects of OPs than to AChE-mediated effects.

• Klíčová slova
• Acetylcholinesterase, Cytotoxicity, Neuroprotection, Neurotoxicity, Organophosphates, SH-SY5Y,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nervová bojová látka * MeSH
• neuroblastom * MeSH
• neurotoxické syndromy * etiologie   MeSH
• protinádorové látky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• nervová bojová látka * MeSH
• protinádorové látky * MeSH
• VX MeSH Prohlížeč

Neuroblastoma cell line SH-SY5Y, due to its capacity to differentiate into neurons, easy handling, and low cost, is a common experimental model to study molecular events leading to Alzheimer's disease (AD). However, it is prevalently used in its undifferentiated state, which does not resemble neurons affected by the disease. Here, we show that the expression and localization of amyloid-β protein precursor (AβPP), one of the key molecules involved in AD pathogenesis, is dramatically altered in SH-SY5Y cells fully differentiated by combined treatment with retinoic acid and BDNF. We show that insufficient differentiation of SH-SY5Y cells results in AβPP mislocalization.

• Klíčová slova
• Alzheimer’s disease, AβPP, SH-SY5Y, differentiation, super-resolution microscopy,
• MeSH
• Alzheimerova nemoc metabolismus   MeSH
• amyloidový prekurzorový protein beta metabolismus   MeSH
• biologické modely MeSH
• buněčná diferenciace fyziologie   MeSH
• intravitální mikroskopie metody   MeSH
• lidé MeSH
• mozkový neurotrofický faktor * metabolismus   farmakologie   MeSH
• nádorové buněčné linie MeSH
• neuroblastom MeSH
• neurony fyziologie   MeSH
• oxidační stres MeSH
• proteolýza MeSH
• tretinoin * metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• Názvy látek
• amyloidový prekurzorový protein beta MeSH
• mozkový neurotrofický faktor * MeSH
• tretinoin * MeSH