No genetic variant is a greater risk factor for Alzheimer’s disease than a variant called APOE4. But exactly how the gene stimulates brain damage is a mystery.
A study1 has now bound APOE4 with faulty cholesterol processing in the brain, which in turn leads to defects in the insulating sheaths that surround nerve fibers and facilitate their electrical activity. Preliminary results suggest that these changes could lead to memory and learning deficits. And the work suggests that drugs that restore cholesterol processing in the brain could treat the disease.
“It fits the picture that cholesterol has to be in the right place,” says Gregory Thatcher, a chemical biologist at the University of Arizona in Tucson.
Inheriting a single copy of APOE4 multiplies by 3 the risk of developing Alzheimer’s disease; having two copies increases the odds 8-12 times. Interactions between the protein encoded by APOE4 and sticky plaques of amyloid — a substance linked to brain cell death — in the brain partly explain the connection. But these interactions are not the whole story.
As neuroscientist Li-Huei Tsai of the Massachusetts Institute of Technology (MIT) in Cambridge and colleagues report today in Nature, APOE4 triggers insulating brain cells called oligodendrocytes to accumulate the fatty molecule cholesterol – a type of lipid – in the wrong places.
This interferes with the cells’ ability to coat nerve fibers with a protective covering made of a lipid-rich material called myelin. Electrical signaling in the brain then slows down and cognition usually suffers.
Tsai’s team had previously linked lipid changes to dysfunctions in other cell types, including some that provide structural support to neurons.2 and others that provide immune protection for the brain3. The latest findings add oligodendrocytes and their essential myelin function to the mix.
“It’s really about putting all the pieces together,” says Julia TCW, a neuroscientist at Boston University in Massachusetts.
Cholesterol traffic jam
Working with MIT computational biologist Manolis Kellis, Tsai and her colleagues began by analyzing patterns of gene activity in the tissues of the prefrontal cortex – the brain’s cognitive center – of 32 deceased people who had two, one, or none. copy of APOE4 and a range of Alzheimer’s stories.
When researchers examined APOE4-affected brain cells, they noted abnormalities in many lipid metabolizing systems. But defects in how oligodendrocytes process cholesterol seemed “particularly severe,” Tsai says.
The team created cultures of human oligodendrocytes with various forms of the APOE embarrassed. The cells with the APOE4 The variant, the group found, tended to accumulate cholesterol in internal organelles. They expelled relatively small amounts of cholesterol, which made them less able to form myelin sheaths.
The researchers then treated APOE4-carrying cells with the drug cyclodextrin, which stimulates the elimination of cholesterol. This helped restore myelin formation. The researchers also found that in mice with two copies of APOE4cyclodextrin appeared to remove cholesterol from the brain, improve the flow of cholesterol into myelin sheaths, and boost cognitive performance in animals.
The findings in mice are consistent with the experience of a person with Alzheimer’s disease who took a similar formulation of cyclodextrin under a special drug access program, as reported in 2020 the drug’s maker, Cyclo Therapeutics in Gainesville, Florida. The individual’s cognitive functions remained stable during 18 months of treatment, the company says.
However, cyclodextrin might not be ideal for correcting lipid imbalances in the brain. “It’s kind of like a sledgehammer,” says Leyla Akay, a neuroscientist in Tsai’s lab and co-author of the latest study. “It just depletes the cholesterol from the cells.”
But better therapies may emerge now that Tsai and her team have helped put cholesterol dysregulation on the map in Alzheimer’s disease research. “This study highlights the importance of cholesterol in the brain,” says Irina Pikuleva, a biochemist at Case Western Reserve University in Cleveland, Ohio, “and now we need to try all available strategies to target brain cholesterol.”
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