Energy Shortage in Brain’s Immune Cells Might Explain Alzheimer’s Risk with TREM2 Mutations

A lack of energy in brain cells called microglia might explain why people with mutations in the TREM2 gene are more likely to develop Alzheimer’s disease, according to a mouse study that showed exhausted microglia lacked the capacity to confine amyloid plaques.

By restoring the energy levels in these cells, it might be possible to treat people with this specific genetic makeup. But researchers say their findings might have even wider implications. If it is also possible to make microglia more energized in people with normal brain function, it might turn out to benefit all Alzheimer’s patients, the team at Washington University School of Medicine (WUSC) suggested.

“Everybody has some plaques, but the activity of these cells affects how much damage the plaques do,” Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology and the study’s senior author, said in a press release.

“So if you have dysfunction in these cells, you have an accelerated process of neurodegeneration. If the cells are more functional, you can delay the process,” he said.

The study, “TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease,” is the first to explain why mutations in the TREM2 gene increase the risk for Alzheimer’s.

Microglia — which are also the main immune cell of the brain — play a crucial role in keeping the brain litter-free. With their ability to engulf debris and dead cells, they play a similar role in the brain as macrophage immune cells do in the rest of the body.

In their report, published in the journal Cell, the research team discovered that microglia from TREM2 mutated mice digested and recycled their own proteins. This is a sign that the cells are short on energy. Looking at cells from deceased patients, they noted the same thing.

In earlier research, they had seen that while microglia not carrying TREM2 mutations surround amyloid-beta plaque, those with mutations in the protein did not. This allowed the plaque to spread more extensively, with resulting damage to neighboring neurons.

In an attempt to restore the cells’ energy levels, the team gave TREM2-deficient mice a compound called cyclocreatine for six months.

As they suspected, microglia in mice who were fed the supplement started surrounding the plaques, reducing neuronal damage.

“If you supplement the microglial metabolic capacity, you can reduce a lot of the damage,” said Tyler Ulland, PhD, and first author of the study. “What this shows is that microglia need to be on their game to deal with the threats to the neurons.”

But using cyclocreatine supplements in an attempt to treat one’s own disease is a bad idea, researchers pointed out. Cyclocreatine and the related creatine are sold as dietary supplements to build muscle. But the compounds are linked to heart and kidney disease as well as metabolic problems.

“We strongly advise against going to the store and buying up cyclocreatine for your parents or grandparents,” said Colonna, who is also a professor of medicine. “Taking cyclocreatine, especially for a long time, carries real and serious risks.”

Instead, the researchers are now evaluating other compounds that might boost microglial energy levels without posing other health risks.

Patients with TREM2 mutations make up only a small part of people with a genetically increased risk of Alzheimer’s, and even fewer when considering all sporadic cases of the disease.

Since microglia appear to protect the brain from the disease, researchers speculate that it might be possible to increase that protection by making microglia more active than normal.

“We’re trying to find out now if it is possible to hyperactivate microglia so they have better-than-normal function,” Colonna said.

“If you can only restore normal function, then microglial treatments will be only useful for people who have microglial deficiency. But if you can hyperactivate the microglia, then this therapy could be useful for everybody. It’s an intriguing possibility.”