Amyloid β42 (Aβ42) plays a decisive role in the pathology of Alzheimer's disease. The Aβ42 peptide can aggregate into various supramolecular structures, with oligomers being the most toxic form. However, different Aβ species that cause different effects have been described. Many cell death pathways can be activated in connection with Aβ action, including apoptosis, necroptosis, pyroptosis, oxidative stress, ferroptosis, alterations in mitophagy, autophagy, and endo/lysosomal functions. In this study, we used a model of differentiated SH-SY5Y cells and applied two different Aβ42 preparations for 2 and 4 days. Although we found no difference in the shape and size of Aβ species prepared by two different methods (NaOH or NH4OH for Aβ solubilization), we observed strong differences in their effects. Treatment of cells with NaOH-Aβ42 mainly resulted in damage of mitochondrial function and increased production of reactive oxygen species, whereas application of NH4OH-Aβ42 induced necroptosis and first steps of apoptosis, but also caused an increase in protective Hsp27. Moreover, the two Aβ42 preparations differed in the mechanism of interaction with the cells, with the effect of NaOH-Aβ42 being dependent on monosialotetrahexosylganglioside (GM1) content, whereas the effect of NH4OH-Aβ42 was independent of GM1. This suggests that, although both preparations were similar in size, minor differences in secondary/tertiary structure are likely to strongly influence the resulting processes. Our work reveals, at least in part, one of the possible causes of the inconsistency in the data observed in different studies on Aβ-toxicity pathways.

• Klíčová slova
• Alzheimer´s disease, Amyloid β42, Apoptosis, Cell death, GM1, Necroptosis, Reactive oxygen species,
• MeSH
• Alzheimerova nemoc metabolismus   patologie   MeSH
• amyloidní beta-protein * metabolismus   farmakologie   MeSH
• apoptóza * účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• lidé MeSH
• mitochondrie metabolismus   účinky léků   MeSH
• nádorové buněčné linie MeSH
• nekroptóza účinky léků   MeSH
• neuroblastom * patologie   metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• peptidové fragmenty * farmakologie   MeSH
• reaktivní formy kyslíku * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloid beta-protein (1-42) MeSH Prohlížeč
• amyloidní beta-protein * MeSH
• peptidové fragmenty * MeSH
• reaktivní formy kyslíku * MeSH

We have analyzed the molecular mechanisms of photoinduced cell death using porphyrins with similar structure differing only in the position of the ethylene glycol (EG) chain on the phenyl ring. Meta- and para-positioned EG chains targeted porphyrins to different subcellular compartments. After photoactivation, both types of derivatives induced death of tumor cells via reactive oxygen species (ROS). Para derivatives pTPP(EG)4 and pTPPF(EG)4 primarily accumulated in lysosomes activated the p38 MAP kinase cascade, which in turn induced the mitochondrial apoptotic pathway. In contrast, meta porphyrin derivative mTPP(EG)4 localized in the endoplasmic reticulum (ER) induced dramatic changes in Ca(2+) homeostasis manifested by Ca(2+) rise in the cytoplasm, activation of calpains and stress caspase-12 or caspase-4. ER stress developed into unfolded protein response. Immediately after irradiation the PERK pathway was activated through phosphorylation of PERK, eIF2α and induction of transcription factors ATF4 and CHOP, which regulate stress response genes. PERK knockdown and PERK deficiency protected cells against mTPP(EG)4-mediated apoptosis, confirming the causative role of the PERK pathway.

• MeSH
• apoptóza účinky léků   účinky záření   MeSH
• ethylenglykol chemie   MeSH
• fotochemoterapie * MeSH
• genový knockdown MeSH
• homeostáza účinky léků   účinky záření   MeSH
• iniciační kaspasy metabolismus   MeSH
• kaspasa 2 metabolismus   MeSH
• kinasa eIF-2 nedostatek   genetika   metabolismus   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• nádorové buněčné linie MeSH
• porfyriny chemie   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce účinky léků   účinky záření   MeSH
• stres endoplazmatického retikula účinky léků   účinky záření   MeSH
• subcelulární frakce účinky léků   metabolismus   účinky záření   MeSH
• vápník metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CASP4 protein, human MeSH Prohlížeč
• ethylenglykol MeSH
• iniciační kaspasy MeSH
• kaspasa 2 MeSH
• kinasa eIF-2 MeSH
• mitogenem aktivované proteinkinasy p38 MeSH
• PERK kinase MeSH Prohlížeč
• porfyriny MeSH
• reaktivní formy kyslíku MeSH
• vápník MeSH

Cell death is an essential event in normal life and development, as well as in the pathophysiological processes that lead to disease. It has become clear that each of the main cellular organelles can participate in cell death signalling pathways, and recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. In cells, the ER functions as the organelle where proteins mature, and as such, is very responsive to extracellular-intracellular changes of environment. This short overview focuses on the known pathways of programmed cell death triggering from or involving the ER.

• MeSH
• apoptóza fyziologie   MeSH
• endoplazmatické retikulum metabolismus   fyziologie   MeSH
• lidé MeSH
• oxidační stres fyziologie   MeSH
• sbalování proteinů MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH