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astrocytes Alzheimer's, microglia, ApoE4

Astrocytes: an Alzheimer’s Drug Target?

By Simon Spichak, MSc | May 3rd, 2022

Cells called astrocytes use the protein encoded by ApoE4 — a genetic mutation linked to Alzheimer’s risk — to transport cholesterol in the brain. Could targeting brain cholesterol unlock the cure? 

Imagine you were to build a brain from scratch. What is the first thing you’d think of using as building blocks? You will probably grab a lot of brain cells called neurons, which can connect, exchange signals, and form loops, circuits, and even distinct brain regions, like the hippocampus for memory recall, or the prefrontal cortex for personality. You add a pinch of oligodendrocytes — cells that insulate the long wire-like part of a brain cell. Finally, a smidge of immune cells called microglia to help the brain organize and defend itself. Taking a step back from the masterpiece, this brain is missing roughly half of its mass. Cells called astrocytes make up this missing half. 

The name astrocyte is derived from the Greek word for glue — an apt description for a cell that is crucial for almost any process in the brain. Astrocytes are responsible for providing energy to neurons, clearing and recycling signaling molecules, sweeping up debris and even regulating the rate at which neurons send signals. 

Astrocytes are also responsible for sending fat and cholesterol packages to neurons. These packages can be transported using the ApoE4 protein, which is the greatest genetic risk factor for developing Alzheimer’s. It is no surprise then, that scientists are turning to astrocytes to better understand Alzheimer’s risk and pathology. Here is why astrocytes are such a key piece of the Alzheimer’s puzzle.

Astrocytes: The ‘Tiny Livers of the Brain’

An endocrinologist is a medical specialist that helps people manage their cholesterol, blood pressure and diabetes. While these specialists don’t often study the brain, high cholesterol levels, high blood pressure and diabetes are risk factors for developing Alzheimer’s. 

Heather Ferris, a clinical endocrinologist and scientist at the University of Virginia became interested in the links between astrocytes, cholesterol and Alzheimer’s risk. 

“I call astrocytes the liver of the brain,” Ferris said. “They do a lot of the same things that the liver does for the rest of the body.”  

Specifically, Ferris’s interest lies in the way astrocytes create cholesterol and deliver it to other cells in the brain. Interestingly, lowering cholesterol in the blood using drugs like statins reduces the risk of developing Alzheimer’s, but it isn’t clear why.

“It’s pretty amazing how long we’ve been studying ApoE4 and how much controversy still surrounds it,” Ferris said. Why does it increase the risk of developing Alzheimer’s? This question is still debated among scientists in the field. 

Cholesterol can’t cross into the brain because it is too large. However, it is important to keep neurons working optimally. Astrocytes produce cholesterol on their own and ship it between different cells. People at risk of developing Alzheimer’s will ship packages of cholesterol in the protein which is encoded by ApoE4.

Ferris explained that ApoE4 can transport cholesterol to the cell membrane leading to a cascade that generates amyloid proteins. But if the ApoE4 isn’t carrying any cholesterol, it instead takes it from the neurons and prevents the generation of amyloid plaques. 

Other lipids carried by ApoE4 in the brain may also play important roles in Alzheimer’s, though we’re only at the early stages of peeking into ApoE4. One method for protecting the brain, which is currently being tested in animal models, involves removing cholesterol from the brain to reduce the deposition of amyloid plaques. 

But for now, Ferris also emphasized the importance of lifestyle changes for keeping the astrocytes and the rest of the brain healthy.

Astrocytes: A Target for Treating Alzheimer’s?

There is still a lot of mystery surrounding the role of astrocytes in Alzheimer’s disease, but there is already some evidence that they may be a useful target. While these cells may not provide any useful biomarkers for diagnosis, they do offer a few clues about neurodegeneration. 

Since diet and exercise both impact the metabolism and energy flux within the brain, their interactions affect astrocytes. Furthermore, any existing symptomatic treatments for Alzheimer’s impact both the neurons and astrocytes. The astrocytes work in tandem with neurons, and due to their many distinct metabolic and immune functions, could be given help to return the brain to a balanced state and relieve Alzheimer’s symptoms. 

One such treatment involves the ApoE4 gene and cholesterol metabolism. If the astrocytes are having trouble dealing with the amount of amyloid plaques deposited in the brain, reducing cholesterol production or blocking its transport to neurons would prevent more amyloid from being released. 

In a genetic mouse model of Alzheimer’s, antibodies targeting ApoE4 could reduce amyloid plaque deposition and improve cognitive functions. Other strategies in earlier stages of research involve helping export more cholesterol out of the brain or even destroying some of the ApoE4 proteins within the brain.

Any therapy used to treat Alzheimer’s will undoubtedly help the astrocytes by making their job as housekeepers and defenders a little bit easier. 

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