Study of Alzheimer’s Risk Gene Reveals Potentially Reversible Mechanism

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

Everyone carries two copies of the APOE gene, which comes in three varieties — APOE2, APOE3, and APOE4 — and the specific combination of these seems affect a person’s probability of developing Alzheimer’s disease. APOE2 appears to be protective against the disease while APOE3 is neutral. But APOE4 is one of the clearest genetic links on Alzheimer’s disease, with one copy increasing the risk up to three times and two copies increasing that risk up to ten 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 to break down in fragments in neurons, leading to an accumulation of protein clumps associated with the disease. Previous studies by the MIT team have shown that the gene causes neurons to produce greater amounts of peptides that cause 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 a lot of people carry it, so the hope is that by studying APOE4, that will also give a bigger picture of the basic pathophysiology of Alzheimer’s disease and what basic cell processes have to go wrong in order for it to happen.” 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 look for pathogens or damaged neurons and break them down to protect the vital organ.

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

Importantly, the discovery could open up new potential treatment routes. In tests on cell cultures containing microglia expressing APOE4, the team administered a drug called Triacsin C, which interferes with the formation of lipid droplets. Sure enough, microglia and nearby neurons were able to communicate better after treatment. Triacsin C itself is not suitable for this use in humans, but the team says the proof-of-concept for these types of treatment strategies has potential.

“We can rescue the suppression of neuronal activity by APOE4 microglia, presumably by restoring lipid homeostasis, where fatty acids do not accumulate extracellularly,” said Matheus Victor, lead author of the study.

The research is published in the journal Cell Stem Cell.

Source: MIT

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