The article appeared on August 17th in the print issue of the National Academy of Sciences. The study offers an in-depth understanding of the underappreciated function of brain cholesterol. A recent article by NeuroScience News highlights a study by Scripps Research scientists using advanced imaging to show how cholesterol regulates the production of the brain’s amyloid-beta (Aβ) protein and how it is associated with Alzheimer’s. The role of cholesterol in Alzheimer’s has been indicated in previous studies but never proven because of technological limitations.
Genetic studies have linked the risk of Alzheimer’s to apolipoprotein E, a protein that transports cholesterol. The Scripps study shows that cholesterol sends signals to neurons to determine the amount of Aβ protein to be produced. Accordingly, since apolipoprotein E transports cholesterol to the neurons, it is associated with the risk of Alzheimer’s.
About Aβ
The focus of the Scripps team is on cholesterol’s association with Aβ production. Aβ in the brain of an Alzheimer’s patient forms large aggregates that accumulate in clumps or “plaques”. The role of Aβ in both the disease and a healthy brain continues to be debatable. Yet genetic evidence ties the production of a subtype of Aβ to Alzheimer’s.
The team used super-resolution imaging, which is high-level microscopy technology that allows them to see inside cells and the brains of live mice. They were able to follow the way in which cholesterol regulates the production of Aβ.
The scientists concentrated on cholesterol that was produced in the brain by astrocytes, which are the most numerous cell type in the central nervous system. They found that the cholesterol was transported by apolipoprotein E to neurons’ outer membranes. Once it had been delivered the team realized that the cholesterol was then maintained in clusters and molecules called “lipid rafts”.
Due to the small size of the lipid rafts, they have not been well understood. They cannot be imaged with common light microscopes. But as technology improves, it becomes evident that lipid rafts host signaling molecules that carry out critical cellular functions.
In addition, the protein APP that produces Aβ is also situated in neuronal membranes. The team found that apolipoprotein E, along with its cargo of cholesterol, causes APP to be in contact with the lipid rafts where enzymes cleaving APP that form Aβ can be found.
The scientists found that if they blocked the flow of cholesterol, it would remove APP from contact with the lipid rafts and prevent Aβ production.
Yet Scott Hansen at Scripps Research notes the importance of cholesterol for the brain in such processes as cognition and alertness. He adds that cholesterol could not be entirely eliminated in neurons as it is needed for Aβ production.
About Brain Health
The Scripps team conducted experiments in genetically engineered mice that were programmed to overproduce Aβ and to mimic Alzheimer’s including Aβ plaques.
When astrocyte cholesterol production was shut off, the production of Aβ dropped to an almost normal level, and the Aβ plaques mostly disappeared. In addition, the usual appearance of tangled clusters of the protein tau which is a common sign in engineered mice also disappeared.
A Potential to Prevent Alzheimer’s Progression
The Scripps scientists believe that a new understanding of cholesterol in the production of Aβ merits further exploration of the potential to stop the progression of Alzheimer’s disease.
