Low Doses of HIV Drug Show Promise Treating Alzheimer's Disease

Efavirenz may aid in the breakdown and removal of cholesterol from the brain in Alzheimer’s disease patients.

Small amounts of the anti HIV drug efavirenz were found to stimulate the enzyme CYP46A1, providing key evidence supporting the launch of a proposed clinical trials for the treatment of Alzheimer’s disease.

Scientists from the National Institute of Standards and Technology (NIST) used a cutting edge, atom-substitution technology called hydrogen-deuterium exchange (HDX) to obtain the molecular roadmap.

Using information obtained by NIST scientists, researchers gained insight on the drug’s mechanism of action, which is key for the proposed launch of clinical trials. Researchers analyzed the HDX data and follow-up experiments to determine why tiny doses of efavirenz kicked CYP46A1 into higher gear, and why larger doses had an inhibiting effect. CYP46A1 is responsible for 80% of cholesterol elimination in the brain.

In an analysis published in the Journal of Biological Chemistry, researchers found that when efavirenz is administered in low doses, it binds to a site on CYP46A1, and boosts cholesterol breakdown in another location on the enzyme, an increase enabled by changes in shape initiated by the drug. In higher doses, the drug’s molecules were see to compete with cholesterol for the same binding site.

“(The shape-changing effect of efavirenz) is a classic example of a basic tenet of biology: structure determines function,” said lead researcher Irina Pikuleva.

When the enzyme-drug was used in mouse models, the connection triggered a 40% increase in cholesterol breakdown and removal from the brain. But, researchers noted that the effect is likely to be significantly higher in people, because the enzyme plays a larger disposal role in human brains than mouse brains.

Studies over the course of 15 years pushed the researchers to look for an Alzheimer’s treatment strategy that focuses on stimulating CYP46A1’s capabilities.

Prior studies used genetic manipulations in mouse models of Alzheimer’s disease, which showed increasing enzyme activity reduced the development of plaque or beta amyloids. It also showed improvements in learning and memory, even in normal mice.

Other mouse studies, however, found that suppressing CYP46A1 led to learning deficiencies. Upon further examination, computational simulations and modeling showed there were more than 30 locations on the enzyme that efavirenz may bind to.

Researchers in the current study wanted to reduce the amount of choices, so they partnered with scientists from the Institute for Bioscience and Biotechnology Research and used an HDX analyses. HDX is a process that involves a series of steps that includes locking in the deuterium in the protein, and then breaking the protein into electrically charged fragments to analyze.

Researchers used a mass spectrometer device to measure the mass of the fragments, and determine how quickly the protein pieces exchange hydrogen for deuterium. A fragment exposed to a large amount of water will have a fast exchange rate, while proteins that do not have a slower exchange rate.

“HDX mass spectrometry opens a window that allows you to look in on how proteins behave under physiologically relevant conditions,” said Kyle Anderson, a researcher from the Institute for Bioscience and Biotechnology Research. “It provides the pieces to a puzzle that you can assemble to show how their 3-demensional shape changes over time.”

For the NIST team, they used HDX to compare and contrast CYP46A1 in 4 different states: alone, with only cholesterol, with only efavirenz, and with a combination of cholesterol and efavirenz.

A subsequent analyses of the resulting torrents of experimental data showed where efavirenz attached to the enzyme and how the site adjusted in response. The structural changes gave CYP46A1 the ability to more tightly bind cholesterol molecules compared to when the drug wasn’t present.

Pikuleva’s team was able to confirm the site bindings using HDX and she stated that the findings strongly suggest that at doses a 100 times lower than those prescribed for the treatment of HIV, efavirenz could potentially be an effective therapy for the prevention or slowing of Alzheimer’s disease.

Now, researchers are looking for funding to conduct a clinical trial on humans to examine the effects of efavirenz in small doses.