Anti-amyloidogenic effects of neurosteroids on amyloid-beta (Aβ) fibrils in vitro

Abstract: Alzheimer’s disease is affecting people all over the world at a growing rate. It is believed that a protein called amyloid-β is the cause of the symptoms of the disease. To understand the chemical effect of Alzheimer’s on the brain, focus is put on studying the methionine residue in the active site of the amyloid-β protein which is believed to cause neuronal toxicity and death. Research has simultaneously shown that neurosteroid-concentrations in the body decrease with growing age. By studying the interactions of this protein with neuroprotective neurosteroids we can learn about the mechanism of action that causes the symptoms of Alzheimer’s disease. In this study, three neurosteroids (estradiol, DHEA and DHEA-S) were tested in vitro to measure their effect on toxic Aβ-fibrillisation. The efficiency of fibrillisation after steroid addition was measured using flouroscence spectroscopy with Thioflavin T (ThT) assay. The results showed that all three neurosteroids significantly decreased Aβ-fibrillisation. The most effective steroid was DHEA-S, followed by DHEA and estradiol. Comparing their chemical structures, it was concluded that oxidizing sp2 hybridized oxygen atoms at the C3 position in the basic steroid ring system was the main contributor to the antitoxic effects of these neurosteroids. Moreover, the antitoxic potentials of these neurosteroids may be dependent on the number of oxidizing elements in the C3 position of the ring system. The findings in this study can be further developed to in vivo systems to determine the effect of these steroids against amyloid-β induced toxicity on neuronal cells. Taking their chemical structures into account can also be used for drug development for Alzheimer’s disease.