Study of Alzheimer’s risk gene reveals potentially reversible mechanism

MIT scientists have uncovered a mechanism for how a common genetic risk factor for Alzheimer’s contributes to the disease. It centers on lipid metabolism, and early investigations suggest it could eventually lead to new treatments to slow disease progression.

Everybody carries two copies of the APOE gene, which comes in three variants – APOE2, APOE3 and APOE4 – and the specific combination of these seems to influence a person’s likelihood of developing Alzheimer’s. APOE2 appears to be protective against the disease, while APOE3 is neutral. But APOE4 is one of the clearest genetic links to Alzheimer’s, with one copy increasing the risk by up to three times, and two copies boosting that risk to 10 times.

Exactly how this gene variant influences Alzheimer’s risk is the subject of much research, including the finding that proteins produced by APOE4 tend to break down into fragments in neurons, leading to a build-up of protein clumps associated with the disease. The MIT team’s previous studies have found that the gene causes neurons to produce larger amounts of peptides that induce them to become hyperactive, and that the gene affects the functions of other cells in the nervous system.

“APOE4 is a major genetic risk factor, and many people carry it, so the hope is that by studying APOE4, that will also provide a bigger picture of the fundamental pathophysiology of Alzheimer’s disease and what fundamental cell processes have to go wrong to result in Alzheimer’s disease,” said Li-Huei Tsai, senior author of the study.

For the new study, the researchers focused on microglia, the resident macrophages in the nervous system. These cells scout for pathogens or damaged neurons and break them down to protect the vital organ.

The team discovered that microglia that express APOE4 cannot metabolize lipids properly, leading to a build-up of these fatty molecules, especially cholesterol, in the brain. The team found that this can suppress neuron firing, a symptom of late-stage Alzheimer’s, and increase inflammation, which is thought to contribute to disease progression.

Importantly, the discovery could open new potential treatment pathways. In tests on cell cultures containing microglia that express APOE4, the team administered a drug called Triacsin C, which disrupts the formation of lipid droplets. Sure enough, microglia and nearby neurons were able to communicate better after treatment. Triacsin C itself isn’t appropriate for this use in humans, but the team says that the proof of concept for this kind of treatment strategy has potential.

“We can rescue the suppression of neuronal activity by APOE4 microglia, presumably through lipid homeostasis being restored, where now fatty acids are not accumulating extracellularly,” said Matheus Victor, lead author of the study.

The research was published in the journal Cell Stem Cell.

Source: MIT

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