This is how the Alzheimer’s gene destroys the brain

Gene variants that are risk factors for Alzheimer’s disease APOE4But how genes drive brain damage remains a mystery.

Investigation¹ now linked APOE4 Impaired cholesterol processing in the brain causes defects in the insulating sheath that surrounds nerve fibers and facilitates electrical activity. Preliminary results suggest that these changes can cause memory and learning deficits. I’m here.

“This fits the picture that cholesterol needs to be in the right place,” says Gregory Thatcher, a chemical biologist at the University of Arizona at Tucson.

bland fat

single-copy inheritance of APOE4 About three times the risk of developing Alzheimer’s disease. With two copies, your chances are 8 to 12 times higher.interactions between proteins encoded by APOE4 Adhesive plaques of amyloid (a substance associated with brain cell death) in the brain partly explain the relationship. But those interactions aren’t everything.

As neuroscientist Li-Huei Tsai and her colleagues at the Massachusetts Institute of Technology (MIT) in Cambridge reported today, Nature, APOE4 It triggers the insulator-making brain cells known as oligodendrocytes to accumulate fat molecules cholesterol, a type of lipid, in the wrong places.

This interferes with the ability of cells to coat nerve fibers with a protective wrapper made of a lipid-rich material called myelin.

Tsai’s team had previously linked lipid changes to dysfunction in other cell types.² Others that provide brain immune protection³The latest findings add oligodendrocytes and their essential myelin functions to the mix.

Julia TCW, a neuroscientist at Boston University in Massachusetts, said:

cholesterol congestion

Working with computational biologist Manolis Kelis at MIT, Tsai and her colleagues studied tissue in the prefrontal cortex (the cognitive center of the brain) of 32 deceased individuals who had two, one, or no copies. We started by analyzing gene activity patterns. APOE4 and a history of contiguous Alzheimer’s disease.

Researchers have found APOE4-Affected brain cells, they noted abnormalities in many systems for metabolizing lipids. says Tsai.

The team created cultures of human oligodendrocytes in different forms appointment gene.cells with APOE4 The variants the group found tended to accumulate cholesterol within internal organelles. They excreted a relatively small amount of cholesterol, which reduced their ability to form myelin sheaths.

The researchers then APOE4– Carries cells with the drug cyclodextrin, which stimulates the removal of cholesterol. This helped restore myelination.The researchers also found that in mice with two copies of APOE4cyclodextrins appeared to flush cholesterol out of the brain, improve cholesterol flow into the myelin sheath, and enhance cognitive performance in animals.

cholesterol buster

The findings in mice are consistent with the experience of Alzheimer’s patients who received similar formulations of cyclodextrin under special drug access programs, as reported by the pharmaceutical company Cyclo Therapeutics in Gainesville, Fla., in 2020. I am doing it. According to the company, the patient’s cognitive function remained stable over his 18-month treatment period.

But cyclodextrins may not be ideal for correcting lipid imbalances in the brain. says Leila Akai, co-author of the study. “It just depletes the cholesterol from the cells.”

But now that Tsai and her team have helped put cholesterol dysregulation on the research map of Alzheimer’s disease, better treatments may emerge. It’s a highlight,” says Irina Pikuleva, a biochemist at Case Western Reserve University in Cleveland, Ohio.