A gene known to be the strongest risk factor for Alzheimer’s disease (AD) alters the way cholesterol moves through the brain, and as we age, this altered movement likely contributes to learning loss and memory, a team of researchers from the Icahn School of Medicine at Mount Sinai and the Massachusetts Institute of Technology (MIT) reports.
The change in cholesterol processing caused by the gene, APOE4may play a central role in cognitive impairment in Alzheimer’s disease, and pharmacological intervention to reduce this effect improved learning and memory in affected mice APOE4 Alzheimer’s disease, according to researchers. The study was published online November 16 in Nature.
Since APOE4 is present in approximately 50% of people with Alzheimer’s, we realized that deciphering its molecular and cellular pathways could help us better understand the pathogenesis of the disease and reveal new therapeutic strategies for a large part of the population. suffering from Alzheimer’s disease. We learned that APOE4 causes changes in gene expression in all cell types of the human brain and significantly alters signaling pathways associated with cholesterol balance and transport. »
Joel Blanchard, PhD, co-lead author, assistant professor of neuroscience and cell, developmental, and regenerative biology, at Icahn Mount Sinai
The study was initiated while Dr. Blanchard was a postdoctoral fellow at the Picower Institute for Learning and Memory in the lab of Li-Huei Tsai, PhD, Picower Professor of Neuroscience at MIT and lead author of the paper. . They continued the collaborative work when Dr. Blanchard joined Mount Sinai as a faculty member in 2021.
“Growing evidence shows that APOE4 disrupts how different brain cells process lipids, including cholesterol, and that this underlying biology may contribute significantly to the pathology of Alzheimer’s disease.” , said Dr. Tsai. “This insight suggests that in a large patient population, lipid regulation may be an attractive target in the urgent search for potential interventions.”
Dr. Blanchard and co-lead authors Leyla Akay and Djuna von Maydell, graduate students at MIT, and Jose Davila Velderrain, PhD, research group leader at Human Technopole, performed single-nucleus RNA sequencing of the prefrontal cortex post-mortem of 32 human brains of people with and without APOE4. The researchers found that in patients with APOE4, cholesterol was aberrantly deposited in oligodendrocytes, the cells responsible for producing myelin, an insulating fatty structure that coats neurons and facilitates electrical communication between different parts of the brain. This accumulation of cholesterol in APOE4 oligodendrocytes caused reduced myelination, impeding electrical communication in the brain and potentially leading to dysfunction in learning and memory.
Previous studies have documented myelin damage in many individuals before the onset of Alzheimer’s disease symptoms and found that reduced myelin volume in the fourth and fifth decades of life predicts a greater likelihood high levels of cognitive impairment decades later. The Mount Sinai-MIT team is the first to establish a functional link between APOE4myelination and memory loss.
“It is interesting to hypothesize from our work that the dysregulation of cholesterol-related processes in oligodendrocytes causes a reduction in myelin in the early life of APOE4 carriers, making them particularly vulnerable to amyloid and tau-mediated neurotoxicity that accumulates later. This has clear implications for the treatment and identification of those at risk of developing Alzheimer’s disease,” says Dr. Blanchard, who is a researcher at the Black Family Stem Cell Institute, Friedman Brain Institute and Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai.
APOE4 is associated with increased deposition of amyloid-β proteins that clump together to form plaques and neurofibrillary tau tangles, both of which accumulate between neurons and disrupt their communication function. Although previous research has suggested a link between Alzheimer’s disease and the interaction of abnormal tau protein and amyloid-β, it remains unclear whether these proteins are the cause or consequence of AD.
The link discovered by Mount Sinai and MIT researchers between APOE4 and cholesterol imbalance could potentially open the door to new therapeutic solutions for a disease known to afflict one in ten Americans over the age of 65.
Dr. Blanchard said that in addition to drugs that facilitate cholesterol transport, other interventions aimed at restoring cholesterol balance in the brain; including diet and lifestyle; may also increase cognitive reserves in people with APOE4 embarrassed. “By identifying the means APOE4 intervenes in the risk of Alzheimer’s disease,” he says, “we have opened up new avenues to treat and prevent the disease with a much-needed non-amyloid strategy.”
Mount Sinai Health System
Blanchard, J.W. et al. (2022) APOE4 impairs myelination via dysregulation of cholesterol in oligodendrocytes. Nature. doi.org/10.1038/s41586-022-05439-w.
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