New research suggests an anti-HIV drug may treat Alzheimer’s by influencing the action of particular enzymes involved in cholesterol clearance. Researchers found certain molecules in efavirenz boost this process and have the potential to improve memory and cognition in individuals with the condition. This direction was partly based on previous research, which showed how cholesterol enzymes may clear the characteristic plaques; beta amyloids, believed to be a highly significant contributor to the Alzheimer’s condition. This plaque removal was shown to improve the memory and cognitive capabilities, clearing the protein between cells and improving signalling. Notably, when plaque-free mice are given a cholesterol enzyme inciting treatment, the cholesterol clearance improves the memory.
Further support for this idea came from a study on mice with decreased genetic expression of the cholesterol enzyme (24-hydroxylase). These mice displayed learning and memory deficits. The RNA interference of the gene resulted in the accumulation of cholesterol in the brains of the mice, which then lead to cognitive deficits and neuronal atrophy. This study further demonstrated how cholesterol within and around neurons contributes to neurodegeneration by creating the conditions necessary to cultivate the recruitment of amyloid protein. When the cyp46a1 gene was inhibited the abundance of the amyloid-b peptides and tau protein characteristic of Alzheimer’s increased.
This provided a firm rationale to the team working on anti-HIV drugs. This new research into cholesterol enzymes illustrates how a drug suitable as an anti-HIV treatment may also be suitable for the alleviation of Alzheimer’s. Efavirenz does this by stimulating an enzyme called cytochrome to operate at an increased level. Cytochrome’s main function is to regulate the cholesterol clearance from the brain. Tests on mice showed a 40% increase in enzyme cholesterol elimination from the brain after treatment with Efavirenz. In this study this also had the effect of improving the memory and learning of the mice and decreased Alzheimer’s like symptoms and neuronal atrophy. The team were optimistic about this finding as the enzyme has a greater role in the human brain suggesting it may be even more effective.
The drug achieves this because of an integral feature of biology. When an effector molecule interacts with an enzyme it regulates its biological activity. A change in the shape of the molecule results from this interaction and may enhance or inhibit a proteins activity. This may be particularly important in a cells ability to alter enzyme activity. “The shape changing effect of efavirenz is a classic example of a basic tenet of biology — structure determines function,” said lead author Irena Pikuleva. A particular enzyme usually focuses on a particular substrate to act upon and may be at a required level of activity to clear a specific substrate or be underactive. A change in the shape of the molecule results from this interaction and may enhance or inhibit the proteins activity, in this case the cholesterol enzyme.
The effects of efavirenz on the enzymes were seen by utilising a dynamic new technology called hydrogen-deuterium exchange (HDX). “HDX mass spectrometry opens a window which allows you to look in on how proteins behave under physiologically relevant conditions,” Anderson says. “It provides the pieces to a puzzle which you might assemble to show how their three-dimensional shape changes over time.” To further demonstrate the changes taking place the team analysed the crystal structure of the enzyme in transition noting significant conformational change transformations.
These cholesterol enzymes may be important in the brain and several aspects of brain function depend on this cholesterol turnover. This includes the formation of neurons in development, neuronal repair, learning and memory. The reason for these enzymes being underactive is still to be found although may be age related as brain cells must accurately maintain cholesterol levels. The study on Efavirenz represents a clear direction for the prevention of Alzheimer’s in humans. By reducing the level of cholesterol the drug may prevent the build-up of plaques, memory deficiencies and Alzheimer’s. By influencing the cyp46a1 enzyme, which may have a greater role and heightened benefit in humans, this may be achieved.
Might Alzheimer’s be largely eradicated in the future?