| Abstract |
AD is the most common neurodegenerative disease characterized by various neuropathological hallmarks including amyloid plaque deposits and neurofibrillary tangles. Other AD-related pathologies are neural stem cell (NSCs) proliferation potential decrease, neuronal loss, demyelination and axonal cytoskeleton lesions. According to amyloid hypothesis Ab peptide seems to play a pathogenic role in AD during which hippocampus and entorhinal cortex (EC) are seriously affected. Another aspect of AD is the low concentration of neurotrophins, which under normal circumstances exert various neuroprotective actions in the brain. The most common neurosteroid in humans, DHEA exerts its neurotrophic actions through binding on NGF neurotrophin receptors TrkA and p75NTR whereas low levels of DHEA are associated with neural dysfunction and degeneration. Nonetheless, the use of natural DHEA as therapeutic agent is compromised, as it is a steroid hormone-precursor molecule, being able to enhance hormone-dependent cancers. For that reason, DHEA C-17 derivatives, such as BNN27, were developed, which sustain their neurotrophic effects, without being hormone-precursors. Using 5xFAD animal model, we investigated the potential effects of BNN27 in 5xFAD brain phenotype, as well as the effects of BNN27 at HNSC cultures treated with synthetic cytotoxic Ab40 and Ab42 oligomers. At the first part of this study, we tested potential effects of BNN27 at Ab plaque formation, demyelination and axonal cytoskeleton at the DG and EC areas of 5xFAD animal brains. First of all, it was demonstrated that BNN27 has little or no effect on myelination and axonal cytoskeleton profiles, whereas the genotype of 5xFAD animals seems to have a strong negative effect on axon, but not on myelin integrity. Secondly, the presence of BNN27 at 5xFAD animal brains showed a significant reduction at amyloid plaque formation at DG area and also a reduction of intracellular Ab accumulation at CA1-CA3 areas. At the second part of the study, the presence of BNN27 in NSC cultures treated or no with different concentrations of cytotoxic Ab40/42 peptide demonstrated an enhancement in the viability of NSCs, but also in the proliferation of them. Together our results indicate that BNN27 neurosteroid analogue has a strong positive effect at 5xFAD animal brains reducing the number of Ab plaques, while it does not seem to affect myelination and axonal cytoskeleton. Furthermore BNN27 seems to obstruct or reverse the cytotoxic effects that oligomeric Ab has on NSCs proliferation. Therefore, it seems that BNN27 could be a potent molecule for therapy strategies targeting either brain Ab plaques or the proliferation of NSCs, which could replace degenerated neurons. Of course, more experiments need to be done towards this direction in order to finally confirm if and how exactly BNN27 interacts NSCs to enhance proliferation, but also how it participates in removing or obstructing Ab plaque formation.
|
Μελέτη των επιδράσεων του αναλόγου νευροστεροειδούς DHEA, BNN27, στο 5xFAD ζωικό μοντέλο για τη νόσο Alzheimer
