Medical

Can Alzheimer's be tackled by cutting cholesterol in the brain?

Can Alzheimer's be tackled by ...
Scientists have uncovered a mechanism that may allow Alzheimer's to be tackled by controlling cholesterol levels in the brain
Scientists have uncovered a mechanism that may allow Alzheimer's to be tackled by controlling cholesterol levels in the brain
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Scientists have uncovered a mechanism that may allow Alzheimer's to be tackled by controlling cholesterol levels in the brain
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Scientists have uncovered a mechanism that may allow Alzheimer's to be tackled by controlling cholesterol levels in the brain
Depletion of cholesterol produced by in astrocyte brain cells (seen on right) leads to a reduction in amyloid plaques and phosphorylated Tau (seen on left in orange clusters) in an Alzheimer’s mouse model
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Depletion of cholesterol produced by in astrocyte brain cells (seen on right) leads to a reduction in amyloid plaques and phosphorylated Tau (seen on left in orange clusters) in an Alzheimer’s mouse model

One interesting area of Alzheimer's research focuses on the relationship between cholesterol in the brain and onset of the disease, with studies suggesting the compound can greatly accelerate the buildup of troublesome brain plaques. A new study has expanded our knowledge of this phenomenon by observing it in action in live mice, with the scientists even finding they could intervene in cholesterol production to make the plaques all but disappear.

The exact triggers of Alzheimer's disease are unknown, but one of the leading hypotheses is that the abnormal buildup of toxic plaques in the brain, called amyloid beta (Aβ) and tau, contribute to onset of the disease. Accumulation of these protein clusters and tangles in and around brain cells impacts cognitive function, and a great deal of research into Alzheimer's therefore focuses on how these form and how they might be avoided.

In 2018, a study provided evidence that cholesterol in the brain could play a fundamental role in the formation of amyloid beta clusters. More specifically, in vitro modeling showed that cholesterol in the membrane lipids surrounding the cells in the brain can accelerate the aggregation of amyloid beta molecules by a factor of 20.

In a new study, a team led by scientists at Scripps Research has leveraged cutting-edge imaging tools to go in for a closer look and gather new evidence that amyloid beta buildup is tightly linked with cholesterol in the brain. The research reveals the details of a signaling chain that leads to heightened production of the problematic proteins, and highlights the important role essential helper cells called astrocytes play in the process.

Using super-resolution microscopy imaging, the scientists studied brain cells in live mice, focusing on the cholesterol produced by astrocytes. This showed that the astrocytes are carried to the outer membrane of neurons by apoE proteins, where they promote the buildup of cholesterol and other molecules known as lipid rafts. Lipid rafts are seen as hubs for other cells to congregate and control key cellular functions.

Also found in the neuronal membranes is a protein called APP, which produces amyloid beta. As apoE enters the area along with its astrocytes and other cargo, APP is put into contact with the lipid rafts, which is where and when the production of amyloid beta takes place. This point of contact is therefore key to the overall process, and is what the scientists took aim at in their next round of experiments.

Aged mice that were genetically engineered to overproduce amyloid beta and develop troublesome plaques were used as a model for Alzheimer's. The scientists shut down the supply chain by which this type of cholesterol is produced in the brain and watched the amyloid beta levels plummet to near normal, and the plaques virtually disappear. The intervention had a similar effect on the aggregation of tau.

Depletion of cholesterol produced by in astrocyte brain cells (seen on right) leads to a reduction in amyloid plaques and phosphorylated Tau (seen on left in orange clusters) in an Alzheimer’s mouse model
Depletion of cholesterol produced by in astrocyte brain cells (seen on right) leads to a reduction in amyloid plaques and phosphorylated Tau (seen on left in orange clusters) in an Alzheimer’s mouse model

“We showed that cholesterol is acting essentially as a signal in neurons that determines how much Aβ gets made – and thus it should be unsurprising that apoE, which carries the cholesterol to neurons, influences Alzheimer’s risk,” says study co-senior author Scott Hansen.

The research sheds yet more light on the relationship between cholesterol and proteins linked to Alzheimer's disease, and throws up some interesting possibilities around how its progression could be slowed. The sticking point in all of this, however, is that that cholesterol is vital for the brain to function properly.

“You couldn’t just eliminate cholesterol in neurons, cholesterol is needed to set a proper threshold for both Aβ production and normal cognition,” Hansen says.

The scientists are now exploring how all of this fits in with genetic risks and other underlying factors for Alzheimers, including inflammation in the brain.

“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,” Hansen says.

The research was published in the journal Proceedings of the National Academy of Sciences (PNAS).

Source: Scripps Research

1 comment
1 comment
MarkGovers
Could it be that the body is using cholesterol as a glue to repair inflamed areas? Perhaps the root cause is inflammation. I am imagining an anti-inflammatory "brain flush" therapy could work wonders.