This Is How an Alzheimer’s Gene Ravages the Brain

This Is How an Alzheimer’s Gene Ravages the Brain

Nature

Study in cells and mice suggests that the variant APOE4 affects the all-important insulation around nerve cells

Illustration of amyloid plaques among neurons and neurofibrillary tangles inside neurons, characteristic hallmarks of Alzheimer’s disease pathology. Credit: Kateryna Kon/Science Photo Library/Getty Images

No gene variant is a bigger risk factor for Alzheimer’s disease than one called APOE4. It is still unknown how this gene causes brain damage.

A study has now linked APOE4 with faulty cholesterol processing in the brain, which in turn leads to defects in the insulating sheaths that surround nerve fibres and facilitate their electrical activity. These changes could lead to learning and memory problems, according to preliminary results. The work suggests that drugs that improve brain cholesterol processing could be used to treat the disease.

” This fits in with the picture of cholesterol needing to be in the right places,” says Gregory Thatcher, a chemical biologist at the University of Arizona in Tucson.

Insipid lipids

Inheriting a single copy of APOE4 raises the risk of developing Alzheimer’s around 3-fold; having two copies boosts the chances 8- to 12-fold. Interactions between the protein encoded by APOE4 and sticky plaques of amyloid–a substance tied to brain cell death–in the brain partially explain the connection. These interactions are only part of the story.

As neuroscientist Li-Huei Tsai at the Massachusetts Institute of Technology (MIT) in Cambridge and her colleagues report today in Nature, APOE4 triggers insulation-making brain cells known as oligodendrocytes to accumulate the fatty molecule cholesterol–a type of lipid–in all the wrong places.

This interferes with cells’ ability to wrap nerve fibers in a protective myelin-rich material called myelin. The brain’s electrical signalling slows down, and cognition is often affected.

Tsai had previously linked lipid modifications to malfunctions within other cell types, such as those that provide structural support to neurons or immune protection for the brain. The latest findings include oligodendrocytes, and their essential myelin function.

” “It’s really putting all the pieces together,” Julia TCW, a neuroscientist from Boston University in Massachusetts, says.

Cholesterol traffic jam

Working with MIT computational biologist Manolis Kellis, Tsai and her colleagues started by analysing gene activity patterns in tissue from the prefrontal cortex–the brain’s cognitive centre–of 32 deceased people who had two, one or no copies of APOE4 and a range of Alzheimer’s histories.

When the researchers examined APOE4-affected brain cells, they noted abnormalities in many systems for metabolizing lipids. Tsai states that the defects in how oligodendrocytes process cholesterol were “particularly severe”.

The team created cultures of human oligodendrocytes with various forms of the APOE gene. Cells with the APOE4 variant, the group found, tended to hoard cholesterol inside internal organelles. They were able to expel relatively low levels of cholesterol, which made them less skilled at forming myelin sheaths.

The researchers then treated APOE4-carrying cells with the drug cyclodextrin, which stimulates cholesterol removal. This resulted in the formation of myelin. The researchers also found that in mice with two copies of APOE4, cyclodextrin seemed to flush cholesterol out of the brain, improve the flow of cholesterol into myelin sheaths and boost the animals’ cognitive performance.

Cholesterol buster

The mouse findings dovetail with the experience of a person with Alzheimer’s who took a similar formulation of cyclodextrin under a special drug-access programme, as reported in 2020 by the drug’s manufacturer, Cyclo Therapeutics in Gainesville, Florida. The individual’s cognitive functions remained stable over 18 months of treatment, the company says.

However, cyclodextrin may not be the best choice for correcting brain lipid imbalances. Leyla Akay, a neuroscientist at Tsai’s laboratory and co-author of the new study, says that cyclodextrin is a “sledgehammer”. It just depletes cholesterol cells .”

But there are better treatments now that Tsai’s team has helped to place cholesterol dysregulation on the Alzheimer’s research agenda. “This study highlights the importance of cholesterol in the brain,” says Irina Pikuleva, a biochemist at Case Western Reserve University in Cleveland, Ohio, “and we now need to try all available strategies to target brain cholesterol.”

This article is reproduced with permission and was first published on November 16 2022.

ABOUT THE AUTHOR(S)

    Elie Dolgin is a science journalist in Somerville, Massachusetts.

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