A New Path for Dementia Treatment (Brain Immune Cells, the GAP Pathway, Hormesis)

I thought “poison becomes medicine” was just a vague figure of speech. But a joint team from the Korea Institute of Science and Technology (KIST) and Boston University School of Medicine actually found that pathway. Quinolinic acid, known until now only as a toxic substance in the brain, turns out to boost the cleaning ability of the brain’s immune cells at low concentrations. Having watched similar scenes countless times while running programs with children at a library, I found this result strangely familiar.

Why the brain’s immune cells stop cleaning up

One of the reasons Alzheimer’s dementia is so frightening is that the brain gradually loses its ability to clean itself. In a healthy brain, microglia take on this role. Microglia are immune cells that reside in the brain and act as cleaners, capturing and breaking down debris and toxic proteins around neurons. The problem is that as dementia progresses, these cells gradually lose function.

So why does the brain stop cleaning itself? Starting from this question, the researchers focused on quinolinic acid, a substance produced naturally during the brain’s metabolism. Quinolinic acid is a byproduct of the breakdown of tryptophan, and until now it was known only as a neurotoxin that directly damages neurons when its concentration rises (Source: Korea Institute of Science and Technology (KIST)).

When I first came across this study, my first question was, “How can you use a toxic substance for treatment?” But the researchers’ key idea was simple: concentration is everything. The same substance can be a poison at high concentrations and a protective signal at low concentrations. It was a reversal of thinking.

• Microglia: immune cells that clean up the brain; their function declines as dementia progresses
• Quinolinic acid: a substance produced during brain metabolism; neurotoxin at high concentrations, protective signal at low concentrations
• Amyloid beta: a toxic protein linked to Alzheimer’s dementia that accumulates in the brain as plaques

In short: the core problem in dementia is that microglia, the brain’s cleaners, lose their function, and the dual nature of quinolinic acid depending on concentration offers a new clue for treatment.

The GAP pathway: how the brain revives itself

What the KIST and Boston University team discovered was not just a phenomenon but a specific mechanism, which they named the “GAP” pathway. The GAP pathway is an intracellular signaling flow in which low concentrations of quinolinic acid stimulate microglia, prompting them to capture and break down toxic proteins more efficiently. Put simply, a very small alarm signal acts as the switch that wakes up the brain’s cleaning system.

The researchers gave low doses of quinolinic acid directly to mice modeling Alzheimer’s dementia. The results came much faster than I expected. Within days, amyloid beta plaques in the brain had noticeably decreased, and damaged connections between neurons began to recover. Beyond that, both short-term and long-term memory improved to near-normal levels (Source: Science Times).

Reading these results reminded me of the days I ran “Mikkumso” (a “future, dream, and hope creative studio”), a creativity program at the library. In a completely free environment without any constraints, the children actually lost direction and became scattered. But when I gave them a task with a little tension, like “read this book by next week and write a one-line response,” the kids who grumbled at first would, at some point, get a different look in their eyes and start to focus. The scenes I witnessed firsthand resembled, structurally, the GAP pathway, in which the brain switches into cleaning mode in response to a tiny stimulus.

This phenomenon, in which a small amount of a harmful substance or a moderate stress actually raises the body’s defensive capacity, is called hormesis. Hormesis refers to a biological response in which low-level toxic stimuli paradoxically increase an organism’s resilience and adaptability. It’s a concept long discussed in toxicology and nutrition, but this is close to the first time it has been identified as a specific molecular pathway at the level of the brain’s immune cells.

In short: the GAP pathway is a signaling route by which low concentrations of quinolinic acid activate the microglial cleaning system, and it is the first concrete evidence that the principle of hormesis actually operates in the brain’s immune mechanisms.

What it will take for this discovery to reach dementia treatment

Honestly, this surprised me. With animal results at this level, I thought it isn’t far-fetched to discuss the possibility of clinical application. Dr. Hoon Ryu, a principal researcher at KIST who led the study, explained that “we showed that a metabolite known only to worsen dementia can act as a signal that raises the resilience of the brain’s immune cells at low concentrations.” Another co-corresponding author, principal researcher Hyunbeom Lee, said the team plans to discover therapeutic candidates that selectively activate the cleaning system of microglia, and to pursue preclinical validation and technology transfer in partnership with pharmaceutical and biotech companies.

The results were published on July 15, 2025, in the international journal Signal Transduction and Targeted Therapy. It’s a highly cited journal in the fields of cell signaling and targeted therapy, which means the study’s credibility has been vetted by the international scientific community.

In my view, this is the different part. For decades, dementia drug development focused on directly removing amyloid beta and repeatedly stumbled at the clinical stage. This approach goes in a different direction altogether: reviving the brain’s own ability to clean itself, that is, restoring phagocytosis by microglia, the brain’s built-in self-cleaning system. Phagocytosis is the process by which cells engulf and break down debris and waste directly; when it works properly, the brain can keep toxic proteins from building up on its own.

The researchers themselves also mentioned the possibility of applying this principle to other degenerative brain diseases caused by the buildup of toxic proteins, such as Parkinson’s disease and ALS. Of course, the road from animal studies to humans is still long and hard. But the fact that the pathway itself has been identified: that is the real weight of this study.

In short: identifying the GAP pathway is the starting point for a new dementia treatment strategy that directly activates the brain’s self-cleaning system, with the potential to extend to other degenerative brain diseases.

Frequently asked questions

Quinolinic acid is toxic. Is it safe to use for treating dementia?

The key is “concentration.” Quinolinic acid acts as a neurotoxin at high concentrations, but this study used low concentrations. The researchers draw this distinction clearly, and they plan to check appropriate concentrations and safety separately as they discover therapeutic candidates and carry out preclinical validation. It’s important to be clear that this is not a substance being used clinically right now.

How is the GAP pathway different from existing dementia drugs?

Most existing approaches have tried to remove amyloid beta directly from outside or to suppress its production. The GAP pathway goes in a different direction: it activates microglia, the brain’s own immune cells, so that the brain handles toxic proteins by itself. You can think of it as switching the brain’s self-cleaning system back on.

If this is an animal study, how long until it can be applied to people?

Generally, it often takes more than ten years to go from animal studies to clinical use, because a candidate has to pass preclinical toxicity testing and phase 1, 2, and 3 clinical trials. But because this study identified the pathway itself, the timeline could vary depending on how quickly candidates targeting this pathway are discovered.

Does the principle of hormesis apply to everyday life too?

In my experience, yes. Exercise is a stimulus that causes tiny damage to muscles, and fasting is a stress that switches on the cell’s autophagy. As this study shows, the brain too seems to work better amid finely tuned, moderate stimulation than in perfect comfort. Of course, the standard for “moderate” is the key, and that is also where more research is needed.

Conclusion

The phrase I lingered on longest in this KIST study was “a metabolite known only to worsen dementia.” It suggests that within what we’ve judged to be bad, there may be sides we don’t yet know. The brain, children, and perhaps I myself seem to have worked that way: not in a perfectly controlled environment, but amid moderately unsettling stimuli, the power to solve something on our own finally switched on.

The road to dementia treatment is still long, but I think the discovery of the GAP pathway is a starting point for trusting the brain’s self-cleaning ability again. I plan to keep watching whether this research can pass through the preclinical and clinical stages and lead to actual treatment.

Reference: https://www.sciencetimes.co.kr/nscvrg/view/menu/247?thisPage=5&searchCategory=216&searchSection=&sersYn=&serlYn=&nscvrgSn=262417

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• #dementia
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• #quinolinic
• #acid
• #hormesis