It has long been known that the genetic variant known as APOE4present in one copy in only 25% of the population, and in two copies in 2-3% of the population, is the most significant genetic risk factor for the development of Alzheimer’s disease. What still escapes is why it is: what is the mechanism determined by this variant that makes the onset of dementia more probable? An MIT study just published in Nature he may have found the reason, which has to do with the transport of lipids (fat molecules) in the brain.
The APOE gene can come in different versions (alleles). The most common is APOE3, which does not appear to affect Alzheimer’s risk. Then there is the rarer APOE2, which could provide some form of protection against this disease, and APOE4 which, on the contrary, increases the chances of developing Alzheimer’s. APOE protein is generally responsible for helping transport cholesterol and other types of fat in the blood.
Without protection. The research team coordinated by Li-Huei Tsai and Manolis Kellis, respectively neuroscientist and computational scientist at MIT, has managed to demonstrate that in people who carry one or two copies of the APOE4 variant, a group of cells (the oligodendrocytes) struggles to transport the fat molecules needed to wrap and insulate the axonsthe extensions of neurons that conduct nerve impulses.
Oligodendrocytes are part of the glia, a set of cells that does not produce electrical impulses but which offers logistic support to neurons, keeping them healthy and isolating them with a lipid-based substance called myelin. The lack of this sheath contributes significantly to the symptoms of Alzheimer’s disease and other diseases, because in the absence of “duct tape” the communications between neurons degrade.
Poorly distributed fat. In recent studies, the same research group had shown that APOE4 also hinders the management of lipids in other brain cells, such as neurons, astrocytes and the immune cells of microglia. The new analyzes were conducted on postmortem brain tissue from 32 people (without, with only one or two copies of the APOE4 variant, 8 of whom died with Alzheimer’s), on cell cultures in the laboratory and finally on mice carrying one or two copies of the gene “indicted”. In the brains of people with APOE4 it was possible to observe enormous quantities of cholesterol accumulated in the cell body, especially in oligodendrocytes, compared with little fat where they were needed, namely around the axons.
No way out. When they recreated cell cultures from patients’ stem cells in the laboratory, the researchers saw that the oligodendrocytes of people with APOE4 actually accumulated lipids inside their membrane and became engulfed in them, but were unable to transport them outside the membrane. membrane and supply them to the axons. When these cells were placed side by side with neurons in the same tube, they failed to coat their tails in myelin, as cells with APOE3 did. The more copies of the gene that were altered, the greater the difficulty in transporting fat.
Pharmacological treatments. It is no coincidence that both in the brains of deceased patients and in mice with APOE4, the myelin sheaths around the axons of the corpus callosum, i.e. the structure that connects the two cerebral hemispheres, were visibly thinner. At this point the scientists tried to understand if drugs commonly used to treat cholesterol, such as statins (which suppress its synthesis) or cyclodextrins (which promote its transport) could help the struggling oligodendrocytes. Statins had no effect, but cyclodextrins, in the laboratory, reduced the accumulation of fat in cells and favored myelination of nearby neurons. Positive effects were found both on myelination and consequently on the memory of mice with APOE4 treated with these drugs.
Hope. It is too early to say whether there will be benefits for patients and which ones, but the study seems to suggest a possible therapeutic avenue for people with APOE4, which targets the regulation of lipids by nerve cells. This could help counteract the symptoms of Alzheimer’s.