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

Amyloid β is considered a key player in the development and progression of Alzheimer's disease (AD). Many studies investigating the effect of statins on lowering cholesterol suggest that there may be a link between cholesterol levels and AD pathology. Since cholesterol is one of the most abundant lipid molecules, especially in brain tissue, it affects most membrane-related processes, including the formation of the most dangerous form of amyloid β, Aβ42. The entire Aβ production system, which includes the amyloid precursor protein (APP), β-secretase, and the complex of γ-secretase, is highly dependent on membrane cholesterol content. Moreover, cholesterol can affect amyloidogenesis in many ways. Cholesterol influences the stability and activity of secretases, but also dictates their partitioning into specific cellular compartments and cholesterol-enriched lipid rafts, where the amyloidogenic machinery is predominantly localized. The most complicated relationships have been found in the interaction between cholesterol and APP, where cholesterol affects not only APP localization but also the precise character of APP dimerization and APP processing by γ-secretase, which is important for the production of Aβ of different lengths. In this review, we describe the intricate web of interdependence between cellular cholesterol levels, cholesterol membrane distribution, and cholesterol-dependent production of Aβ, the major player in AD.

• Klíčová slova
• Amyloid precursor protein, Amyloid β, Amyloidogenesis, Cholesterol, Secretase,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Muscarinic acetylcholine receptors expressed in the central nervous system mediate various functions, including cognition, memory, or reward. Therefore, muscarinic receptors represent potential pharmacological targets for various diseases and conditions, such as Alzheimer's disease, schizophrenia, addiction, epilepsy, or depression. Muscarinic receptors are allosterically modulated by neurosteroids and steroid hormones at physiologically relevant concentrations. In this review, we focus on the modulation of muscarinic receptors by neurosteroids and steroid hormones in the context of diseases and disorders of the central nervous system. Further, we propose the potential use of neuroactive steroids in the development of pharmacotherapeutics for these diseases and conditions.

• Klíčová slova
• Alzheimer’s disease, Parkinson’s disease, cholesterol, depression, muscarinic receptors, neuroactive steroids, neurosteroids, schizophrenia, substance abuse,
• MeSH
• centrální nervový systém MeSH
• cholinergní látky MeSH
• hormony MeSH
• neurosteroidy * farmakologie   MeSH
• receptory muskarinové MeSH
• steroidy farmakologie   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• cholinergní látky MeSH
• hormony MeSH
• neurosteroidy * MeSH
• receptory muskarinové MeSH
• steroidy MeSH