Brain's 'cleanup cells' awakened by low doses of toxic compound to clear Alzheimer's protein

- KIST identifies for first time how low-concentration quinolinic acid activates microglia's waste-clearing function

- Amyloid beta reduced and neural connections restored in Alzheimer's mice, raising hopes for new treatment

A brain metabolite long regarded as a toxin that worsens dementia has been found, at low concentrations, to do the opposite — awakening the brain's "cleanup cells" and prompting them to clear the proteins responsible for Alzheimer's disease.

The Korea Institute of Science and Technology said Tuesday that a research team led by principal researchers Ryu Hun and Lee Hyun-bum, working with a team led by Professor Lee Jung-hee at Boston University School of Medicine, had identified a new pathway that enhances the waste-clearing capacity of microglia, the brain's immune cells. Ryu is based at KIST's Brain Disease Research Center and Lee Hyun-bum at its Biomolecular Recognition Research Center.

Alzheimer's disease is a degenerative brain disorder in which toxic proteins such as amyloid beta accumulate in the brain and damage nerve cells. The brain's natural ability to clear waste declines with age, and that deterioration is widely considered one of the key factors making the disease so difficult to treat.

The research team focused on quinolinic acid (QA), a metabolite found in the brain. At high concentrations, quinolinic acid is neurotoxic. The team became the first in the world to confirm, however, that at low concentrations it actually enhances microglia's ability to remove waste.

When low-concentration quinolinic acid stimulates microglia, it activates a key enzyme involved in producing phospholipids, which make up the cell membrane. The phospholipids generated through this process make the cell membrane more flexible and bind with an autophagy-related protein called GABARAP, helping microglia capture and break down toxic proteins more effectively.

The phenomenon — in which a small amount of a harmful substance boosts the body's defenses — is known as the "hormesis" effect. The team named the newly discovered cleanup pathway GAP, for GABARAP-Associated Phagocytosis.

The study demonstrates that activating GABARAP-mediated phagocytosis (GAP) through regulation of the phospholipid synthesis pathway in microglia is a key mechanism for effectively clearing amyloid beta (Aβ) from the Alzheimer's brain. [Provided by KIST]

Animal experiments confirmed the effect. When low-concentration quinolinic acid was administered locally to the brains of mice with Alzheimer's disease, amyloid beta plaques in the hippocampus — the region responsible for memory — decreased significantly within days. Damaged neural connections were restored, and both short- and long-term memory improved to levels comparable to those of healthy mice.

Rather than using quinolinic acid itself as a treatment given its toxicity, the team believes it will be possible to develop a therapy that selectively activates only the brain's cleanup system that quinolinic acid triggers. The researchers said the approach could also apply to other degenerative brain diseases caused by the accumulation of toxic proteins, including Parkinson's disease and Huntington's disease.

"We confirmed that a metabolite known only as a substance that worsens dementia can, at low concentrations, act as a signal that enhances the resilience of the brain's immune cells," Ryu said. "We have proposed a new treatment strategy for dementia that leverages the metabolic and waste-clearing functions of those immune cells."

He added that bringing a treatment to practical use would require safety validation and clinical trials in humans, building on the amyloid beta clearance and cognitive recovery results demonstrated in genetically modified mouse models.

The findings were published in the latest issue of the international journal Signal Transduction and Targeted Therapy.

nbgkoo@heraldcorp.com