Brain Cholesterol May Play Important Role in Onset of Alzheimer’s Disease

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A research team led by a University of Cambridge scientist has found that in the brain, cholesterol acts as a catalyst which triggers the formation of the toxic clusters of the amyloid-beta protein, a central player in the development of Alzheimer’s disease. It is unclear, however, if the results — published in the journal Nature Chemistry — have any implications for dietary cholesterol, as cholesterol does not cross the blood-brain barrier.

Alzheimer’s disease is a progressive neurodegenerative disease, characterized clinically by progressive memory loss, cognitive decline, and aberrant behavior. In Alzheimer’s, changes in tau protein lead to the disintegration of microtubules in brain cells. Image credit: Alzheimer’s Disease Education and Referral Center / National Institute on Aging.

Alzheimer’s disease is a progressive neurodegenerative disease, characterized clinically by progressive memory loss, cognitive decline, and aberrant behavior. In Alzheimer’s, changes in tau protein lead to the disintegration of microtubules in brain cells. Image credit: Alzheimer’s Disease Education and Referral Center / National Institute on Aging.

University of Cambridge’s Professor Michele Vendruscolo and co-authors found that cholesterol, which is one of the main components of cell walls in neurons, can trigger amyloid-beta molecules to aggregate.

The aggregation of amyloid-beta eventually leads to the formation of amyloid plaques, in a toxic chain reaction that leads to the death of brain cells.

While the link between amyloid-beta and Alzheimer’s disease is well-established, what has baffled researchers to date is how amyloid-beta starts to aggregate in the brain, as it is typically present at very low levels.

Professor Vendruscolo said: “the levels of amyloid-beta normally found in the brain are about a thousand times lower than we require to observe it aggregating in the laboratory — so what happens in the brain to make it aggregate?”

Using a kinetic approach, the researchers found in in vitro studies that the presence of cholesterol in cell membranes can act as a trigger for the aggregation of amyloid-beta.

“Since amyloid-beta is normally present in such small quantities in the brain, the molecules don’t normally find each other and stick together,” the scientists said.

“Amyloid-beta does attach itself to lipid molecules, however, which are sticky and insoluble.”

“In the case of Alzheimer’s disease, the amyloid-beta molecules stick to the lipid cell membranes that contain cholesterol.”

Once stuck close together on these cell membranes, the amyloid-beta molecules have a greater chance to come into contact with each other and start to aggregate — in fact, they found that cholesterol speeds up the aggregation of amyloid-beta by a factor of 20.

So what, if anything, can be done to control cholesterol in the brain?

“It’s not cholesterol itself that is the problem,” Professor Vendruscolo said.

“The question for us now is not how to eliminate cholesterol from the brain, but about how to control cholesterol’s role in Alzheimer’s disease through the regulation of its interaction with amyloid-beta.”

“We’re not saying that cholesterol is the only trigger for the aggregation process, but it’s certainly one of them.”

Since it is insoluble, while traveling towards its destination in lipid membranes, cholesterol is never left around by itself, either in the blood or the brain: it has to be carried around by certain dedicated proteins, such as ApoE, a mutation of which has already been identified as a major risk factor for Alzheimer’s disease.

As we age, these protein carriers, as well as other proteins that control the balance, or homeostasis, of cholesterol in the brain become less effective.

In turn, the homeostasis of amyloid-beta and hundreds of other proteins in the brain is broken.

By targeting the newly-identified link between amyloid-beta and cholesterol, it could be possible to design therapeutics which maintain cholesterol homeostasis, and consequently amyloid-beta homeostasis, in the brain.

“This work has helped us narrow down a specific question in the field of Alzheimer’s research. We now need to understand in more detail how the balance of cholesterol is maintained in the brain in order to find ways to inactivate a trigger of amyloid-beta aggregation,” Professor Vendruscolo said.

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Johnny Habchi et al. Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes. Nature Chemistry, published online May 7, 2018; doi: 10.1038/s41557-018-0031-x