engleski

Potential therapeutic interventions targeting amyloid beta toxicity (in vitro model of Alzheimer ´s disease)

Alzheimer´s disease (AD) is a progressive neurodegenerative disorder that accounts for about 70% of all dementia cases. The AD pathogenesis is characterized by the aggregation of amyloid β (Aβ) peptides into extracellular senile plaques, and the formation of intracellular neurofibrillary tangles by the hyperphosphorylated tau protein. Although both structures are considered to cause a significant loss of neurons and synapses, the Aβ hypothesis has been the dominant opinion for more than 25 years [1]. The intraneuronal accumulation of Aβ peptides may precede the generation of Aβ plaques and neurofibrillary tangles formation. The Aβ peptides are known to self-assemble into dimer, trimer and higher-order oligomers, which are believed to be the main source of toxicity by causing the death of neurons [2]. Since current therapy (cholinesterase inhibitors donepezil, galantamine and rivastigmine, as well as memantine, an N-methyl D-aspartate receptor antagonist) is still symptomatic, potential disease-modifying treatment strategies have been extensively investigated [3]. In addition to positive effects on overall human health, neurosteroids dehydroepiandrosterone (DHEA) and its sulfated form dehydrepiandrosterone sulfate (DHEAS) [4], as well as neurotrophin brain-derived neurotrophic factor (BDNF) [5], are of a great interest as potential therapeutic targets for AD, due to their involvement in neurogenesis, synaptic plasticity, neuronal growth, differentiation, protection, and survival. In our laboratory, cultured primary neurons derived from C57BL/6 mice were exposed to various Aβ preparations to optimize the in vitro model of AD. To investigate the potential neuroprotective actions against Aβ toxicity, primary neuronal cultures were treated with DHEA/S, BDNF and their combination and their effects on the cell viability and mechanisms of action were studied using various cell-based and biochemical assays. Our results suggesting neuroprotective effects of DHEA/S, BDNF and their combination could point to the new therapeutic interventions for this still incurable disease. However, our findings should be confirmed by further in vitro research, as well as by in vivo experiments using AD animal models and human blood samples.

Alzheimer´s disease ; amyloid beta oligomers ; DHEA ; DHEAS ; BDNF

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