New Alzheimer's Research Sheds Light On 'Garbage Collecting' Proteins

Researchers have linked three genetic risk factors associated with Alzheimer’s disease to an immune cell dysfunction in mice, shedding light on a biochemical mechanism behind the genes. Researchers at Genentech, a biotechnology company based out of San Francisco, published their work in a recent article in the journal Neuron.

Amyloid beta is a protein that has long been known to be a hallmark of Alzheimer’s disease — if you don’t have amyloid beta, you don’t have Alzheimer’s disease. Amyloid beta can clump together — which is thought to be toxic for nerve cells. The new research helps to understand why amyloid beta isn’t properly cleared from the brain.

Think about how a garbage truck goes about collecting trash on your street. There is a garbage truck with a garbage collector hanging off of the back. The garbage collector jumps off the truck and grabs trash cans (by their handles) and throws the trash into the truck. The process studied by the researchers is very similar.

The microglia (immune cells) act as the trash truck. A receptor on it’s surface, called TREM2, acts as the trash collector. They travel around the brain picking up trash, the toxic amyloid beta. But, just like the trash truck, a microglia can’t pick up every piece of trash it sees on the street, it needs to be in a trashcan. In the brain, the trash cans are lipoproteins — proteins attached to lipids (the group of molecule fats are part of) — that bind to amyloid beta. The trashcan’s handles are two proteins that are part of the lipoprotein. The trash collector, TREM2 binds to the handles to clean up the trash, amyloid beta.

Dr. Felix Yeh, the main researcher and a scientist at Genentech, explained in an interview that the trashcan — the lipoprotein — is a beacon for the TREM2/microglia garbage truck.

TREM2, and the “trashcan handle” proteins — called APOE and APOJ—  were all previously known to be genetic risk factors in Alzheimer’s disease but they hadn't been linked until the paper.

After studying the mechanism in mouse cells, Yeh and his colleagues adapted the experiment to human cells. Since microglia are only in the brain, the researchers used a similar cell type that they could find in blood called macrophages. They compared people who had a healthy TREM2 gene against people who had a mutated version — which is associated with Alzheimer’s disease— to see whose cells were better able to clear away the amyloid beta.

Yeh found that human macrophages with healthy TREM2 were better able to collect amyloid beta than those with mutant TREM2. This suggests that the researcher’s findings in mice may hold true in humans.

“The fact that our hypothesis and theory held true in humans when we took human cells was one of the highlights for me,” said Yeh.

Yeh and his colleagues hope that by having a clearer understanding on how TREM2 is involved in Alzheimer’s, treatments that focus on TREM2 can be improved.

For now, the team is working on expanding their results in mouse models.