Key Alzheimer’s gene changes how cholesterol moves in the brain, study finds

A gene, recognized as the strongest risk factor for Alzheimer’s disease (AD), changes the way cholesterol moves around the brain, and as we age, this altered movement contributes to learning and memory loss. likely contribute to, say researchers at the Icahn School of Medicine. Reports from Mount Sinai and the Massachusetts Institute of Technology (MIT).

genetically mediated alterations in cholesterol processing, APOE4may play a central role in Alzheimer’s disease-related cognitive deficits, and pharmacological interventions to mitigate this effect improved learning and memory in mice APOE4 Alzheimer’s disease, researchers said. The study was published online on November 16th. Nature.

ever since APOE4 Present in about 50% of people with Alzheimer’s disease, deciphering its molecular and cellular pathways could help us better understand disease pathogenesis and uncover new therapeutic strategies for a large portion of the AD population. I noticed.we learned that APOE4 It causes gene expression changes in all cell types in the human brain, significantly altering signaling pathways associated with cholesterol balance and transport. ”

Joel Blanchard, PhD, Co-First Author, Assistant Professor of Neuroscience, Cell, Developmental and Regenerative Biology, Icahn Mount Sinai

The research began with Dr. Blanchard as a postdoctoral fellow at the Picower Institute for Learning and Memory in the lab of Dr. Li-Huei Tsai, Picower Professor of Neuroscience and senior author of the paper at the Massachusetts Institute of Technology. When Dr. Blanchard joined Mount His Sinai as a faculty member in his 2021, they continued to work as a collaborative effort.

“There is growing evidence that APOE4 disrupts the way various brain cells process lipids, including cholesterol, and that this underlying biology may significantly contribute to the pathology of Alzheimer’s disease. said Dr. Tsai. “This insight suggests that lipid regulation may be a valuable target in the urgent search for potential interventions in large patient populations.”

Dr. Blanchard, co-lead author Leyla Akay, and MIT graduate student Djuna von Maydell, and Human Technopole research group leader Jose Davila Velderrain, Ph.D. Nuclear RNA sequencing was performed.from those who have and those who do not APOE4. APOE4, cholesterol was abnormally deposited in oligodendrocytes, cells involved in the generation of myelin, the fatty insulating structure that coats neurons and facilitates electrical communication between different parts of the brain.This accumulation of cholesterol APOE4 Oligodendrocytes can result in decreased myelination and interfere with electrical communication in the brain, leading to dysfunction in learning and memory.

Previous studies have documented myelin damage in many individuals before symptoms of Alzheimer’s disease appear, suggesting that reduced myelin mass at 40 and 50 years of age may lead to cognitive impairment decades later. was found to be expected to be higher. The Mount Sinai MIT Team APOE4myelination, and amnesia.

“It is interesting to speculate from our study that dysregulation of cholesterol-related processes in oligodendrocytes causes myelin loss early in life. APOE4 Being carriers, they become particularly vulnerable to later-accumulating amyloid and tau-mediated neurotoxicity. This has clear implications for the treatment of Alzheimer’s disease and the identification of those at risk of developing it.” Mount Sinai.

APOE4 It is associated with increased deposition of amyloid-β protein, which aggregates to form plaques, and neurofibrillary tangles of tau protein, both of which cluster between neurons and disrupt their communication function. Previous studies have suggested a link between Alzheimer’s disease and abnormal tau and amyloid-β interactions, but it is not yet known whether these proteins are the cause or consequence of AD.

Link between Mount Sinai and MIT Researchers Revealed APOE4 Cholesterol imbalance could also open the door to new treatments for diseases known to afflict one in ten Americans over the age of 65.

In addition to drugs that facilitate cholesterol transport, Dr. Blanchard notes that other interventions (including diet and lifestyle) designed to restore cholesterol balance in the brain can also APOE4 gene. “By identifying how APOE4 It mediates the risk of Alzheimer’s disease,” he says.