In a new study, researchers from the Scripps Research Institute, the University of Virginia and the University of Washington used advanced imaging methods to reveal how production of the Alzheimer's disease-associated protein amyloid beta (Aβ) in the brain is tightly regulated by cholesterol.

These findings advance the understanding of how Alzheimer's disease arises and highlight the long-underappreciated role of cholesterol in the brain, in addition to helping explain why genetic studies have linked Alzheimer's disease risk to a cholesterol transporter protein called apolipoprotein E (apoE). Related findings are published in the Aug. 17, 2021 issue of PNAS.

Dr. Hansen said, "We found that cholesterol essentially functions as a signal in neurons that determines how much Aβ is made. So it should be no surprise that apoE, which carries cholesterol to neurons, affects Alzheimer's disease risk."

Aβ in the brains of people with Alzheimer's disease can form large, insoluble aggregates and collect into large clumps or plaques, one of the most prominent features of the disease. Genetic evidence suggests that the production of a subtype of Aβ is associated with Alzheimer's disease, yet the role of Aβ in healthy brains and disease remains a topic of debate, and many previous clinical trials of treatments to clear Aβ have not shown them to be beneficial.

In this new study, these researchers took a closer look at the relationship between cholesterol and Aβ production. The role of cholesterol has been hinted at in various previous studies, but never directly confirmed due to technical limitations. They used an advanced microscopy technique called super-resolution imaging to look in cells and in the brains of mice models ( and track how cholesterol regulates Aβ production. They focused on cholesterol produced in the brain by helper cells called astrocytes and observed that it is carried by the apoE protein to the outer membrane of neurons. It appears to contribute to the maintenance of cholesterol and related molecular clusters, commonly known as lipid rafts that are not well understood, partly because they are too small to be imaged with ordinary light microscopy. As technology improves, they are increasingly recognized as hubs where signaling molecules come together to perform critical cellular functions.

The protein that produces Aβ, amyloid precursor protein (APP), is also located in the neuronal membrane. These researchers found that apoE and its cholesterol cargo put APP in contact with nearby lipid rafts. In the lipid rafts, they found the enzyme that cleaves APP to form Aβ. They found that blocking the flow of cholesterol would disengage APP from contact with lipid rafts, thus effectively preventing Aβ production.

Cholesterol and brain health
These researchers then performed a series of experiments on aged "3xTg-AD" mice that were genetically modified ( to overproduce Aβ, forming Aβ plaques that were widely used to mimic Alzheimer's disease. They found that when cholesterol production by astrocytes in the brains of these mice was turned off, Aβ production dropped dramatically to near normal and Aβ plaques virtually disappeared. Another typical sign of Alzheimer's disease normally observed in these mice was the accumulation of tangled aggregates of a neuronal protein called tau. However, tau also disappeared.

By confirming and elucidating the role of cholesterol produced by astrocytes in Aβ production, this study suggests that the potential of targeting this process to stop the progression of Alzheimer's disease is worth exploring. However, Hansen notes that the brain needs cholesterol for many other processes, including the maintenance of normal alertness and cognitive performance. His lab has already found in a 2020 study that general anesthetics that severely block the action of cholesterol in neurons can induce unconsciousness through a common mechanism (PNAS, 2020, doi:10.1073/pnas.2004259117). Hansen added, "You can't just eliminate neurons from cholesterol, cholesterol needs to set an appropriate threshold for Aβ production and normal cognition."

These findings provide new evidence for the underlying factors that promote the production of Alzheimer's disease. a common variant of the apoE gene, the E4 variant, is the greatest risk factor for late-onset Alzheimer's disease, and it was also found in this study that the E4 variant somehow facilitates the association of app with lipid rafts and thus Aβ production compared with the more common, low-risk E3 variant.

These authors are currently investigating how apoE transports cholesterol and maintains lipid rafts in the brain affecting not only Aβ production but also brain inflammation—another feature of Alzheimer's disease that wreaks havoc on the brain for unknown reasons. Hansen said, "this study proposes a central mechanism involving cholesterol that may help explain why Aβ plaques and inflammation are so prominent in the brains of people with Alzheimer's disease."

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