This Is How an Alzheimer’s Gene Ravages the Brain

no gene variant is a bigger risk factor for alzheimer’s disease than one called apoe4. but exactly how the gene spurs brain damage s'been a mystery.

a study has now linked apoe4 with faulty cholesterol processing inna brain, which in turn leads to defects inna insulating sheaths that surround nerve fibres and facilitate their electrical activity. preliminary results hint that these changes ‘d cause memory and learning deficits. na work suggests that drugs that restore the brain’s cholesterol processing ‘d treat the disease.

“this fits in w'da picture that cholesterol needo be inna rite place,” says gregory thatcher, a chemical biologist atta university of arizona in tucson.

insipid lipids

inheriting a single copy of apoe4 rezs th'risk of developing alzheimer’s round 3-fold; having two copies boosts the chances 8- to 12-fold. interactions tween the protein encoded by apoe4 and sticky plaques of amyloid—a substance tied to brain cell death—inna brain ptially explain the connection. but those interactions aint the whole story.

as neurosci li-huei tsai atta massachusetts institute of tek (mit) in cambridge and her colleagues reprt tody in natureapoe4 triggers insulation-making brain cells known as oligodendrocytes to accumul8 the fatty molecule cholesterol—a type of lipid—in all the wrong places.

this interferes w'da cells’ ability to cover nerve fibres in a protective wrapper made offa lipid-rich material called myelin. electrical signalling inna brain then slos, and cogg usually suffers.

tsai’s team had previously linked lipid changes to malfunctions in other cell types, including some that offer structural support to neurons and others that provide immune protection for the brain. the l8st findings add oligodendrocytes and their primordial myelin function to the mix.

“it’s really pulling all the pieces together,” says julia tcw, a neurosci at boston university in massachusetts.

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 cogg centre—of 32 deceased pplz 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. but defects in how oligodendrocytes processed cholesterol seemed “pticularly severe”, tsai says.

the team created cultures of human oligodendrocytes with various forms of the apoe gene. cells w'da apoe4 variant, the group found, tended to hoard cholesterol inside internal organelles. they expelled relatively lo amounts of cholesterol, which made them less adept at forming myelin sheaths.

the researchers then treated apoe4-carrying cells w'da drug cyclodextrin, which stimul8s cholesterol removal. this helped to restore myelin formation. the researchers also found that in mice with two copies of apoe4, cyclodextrin seemed to flush cholesterol out of the brain, improve the flo of cholesterol into myelin sheaths and boost the animals’ cogg performance.

cholesterol buster

the mouse findings dovetail w'da experience offa'pers with alzheimer’s who took a similar formulation of cyclodextrin under a spesh drug-access programme, as reprted in 2020 by the drug’s manufacturer, cyclo therapeutics in gainesville, florida. the individual’s cogg functions remained stable over 18 mnths of treatment, the company says.

however, cyclodextrin mite not be ideal for correcting lipid imbalances inna brain. “it’s kind of sledgehammer,” says leyla akay, a neurosci in tsai’s lab and a co-author of the l8st study. “it just depletes cholesterol from cells.”

but better therapies ‘d emerge now that tsai and her team ‘ve helped to put cholesterol dysregulation onna alzheimer’s research map. “this study highlites the importance of cholesterol inna brain,” says irina pikuleva, a biochemist at case western reserve university in clvland, ohio, “and we now nd'2 try all available strategies to target brain cholesterol.”

this article is reproduced with permission and was 1st published on nov 16 2022.

original content at:…
authors: elie dolgin, nature magazine