Cholesterol levels in the brain tightly regulate the production of amyloid-beta plaques in the brain, a key feature of Alzheimer's disease. The research was published in PNAS by researchers led by The Scripps Research Institute.
Although the production of amyloid-beta plaques in the brain has been linked to the presence of certain genes, scientists are still not in agreement as to what causes amyloid-beta plaques to form.
Although previous studies have suggested a possible link between amyloid-beta build-ups and cholesterol, technological limitations mean that the link has, until now, not been confirmed. The researchers behind this study decided to investigate the link.
To do so, they used super-resolution imaging, an advanced microscopy technique, to track how cholesterol interacts with amyloid-beta production in the cells and brains of mice.
They found that cholesterol-transporting protein, apolipoprotein E (apoE), carried cholesterol produced by helper cells called astrocytes to the outer membranes of neurons. There, the cholesterol appeared to maintain clusters of cholesterol and similar molecules in what is known as a 'lipid raft'.
APP, a protein key for amyloid-beta production, also sits on neuronal membranes. The researchers saw that apoE and its cholesterol cargo bring APP into contact with nearby lipid rafts, which then cleave APP and form amyloid-beta plaques.
Blocking the flow of cholesterol, observed the researchers, prevented APP from making contact with lipid rafts, and thus prevented the production of amyloid-beta cells.
The researchers then tested their findings on aged mice genetically engineered to overproduce amyloid-beta and develop amyloid-beta plaques similar to those in Alzheimer's disease.
In shutting off astrocyte cholesterol production, amyloid-beta production returned to almost normal levels, and amyloid-beta plaques disappeared. Tangled proteins called tau, also characteristic of Alzheimer's, also disappeared.
While the findings offer new evidence for the underlying factors behind Alzheimer's disease, the researchers warn that cholesterol is still needed for many cognitive processes. Their findings may nevertheless explain why genetic studies have found a link between Alzheimer's and apoE.
"There is the suggestion here of a central mechanism, involving cholesterol, that could help explain why both Aβ plaques and inflammation are so prominent in the Alzheimer's brain," said co-senior author of the paper, Scott Hansen.