New research by MIT scientists shows how microglia contribute to Alzheimer’s disease

• Microglia slow down neuron activity.
• The type of cells also results in the build-up of lipids.
• Treating them may be an effective cure for Alzheimer’s.

Alzheimer’s is a debilitating disorder that is currently being studied across the world in the hopes of preventing its development and curing its symptoms. Now MIT researchers may have found the key to its treatment in a type of cell called microglia.

A reduction in the firing of neurons

It turns out that one of the key side effects of Alzheimer’s is a reduction in the firing of some neurons in the brain, which contributes to the disease’s cognitive decline. Microglia, it turns out, may be responsible for this slowdown of neuron activity, thus being the cause of the disease’s devastating consequences, according to a new report by MIT published on Thursday.

It’s all because of the APOE4 gene expressed by microglia, one of the strongest genetic risk factors for Alzheimer’s disease that makes it so that the human brain cannot metabolize lipids normally. The end result is a build-up of excess lipids that interferes with neurons’ ability to communicate with each other.

“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 in the statement Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study.

The researchers now hope that if they can restore normal lipid metabolism in microglia, they may succeed in treating some of the symptoms of the disease. So far, it has been estimated that people who carry one copy of APOE4 have a threefold higher risk of developing Alzheimer’s, and people with two copies have a tenfold higher risk.

“If you look at this another way, if you look at the entire Alzheimer's disease population, about 50 percent of them are APOE4 carriers. So, it's a very significant risk, but we still don't know why this APOE4 allele presents such a risk,” Tsai says.

Interactions between microglia and neurons

The researchers focused on analyzing how APOE4 affects interactions between microglia and neurons and found that APOE4 disrupts microglia’s ability to metabolize lipids and prevents them from removing lipids from their environment.

This results in the build-up of fatty molecules that bind to a specific type of potassium channel embedded in neuron cell membranes, which suppresses neuron firing and leads to inflammation that contributes to the progression of Alzheimer’s disease.

The researchers are now seeking to find a solution to thwart these processes before they have time to show up as Alzheimer’s’ effects.

“The question is, how do you restore lipid homeostasis across multiple cell types? It's not an easy task, but we're tackling that through choline, for example, which might be a really interesting angle,” Matheus Victor, MIT postdoc and the lead author of the paper, concluded.