Modified zinc finger scaffold suppresses microglial activation in mouse brain

A KAIST-led research team has found that a protein involved in gene regulation can suppress the harmful aggregation of amyloid-beta, a peptide associated with Alzheimer's disease. The approach also reduced the toxicity of protein aggregates that had already formed. In experiments using a mouse model of Alzheimer's disease, the treatment reduced protein accumulation in the brain and improved recognition memory, suggesting a possible route toward new therapeutics.

KAIST (President Choongsik Bae) announced on November 5 that the research team led by Professor Mi Hee Lim from the Department of Chemistry identified a new approach to controlling the aggregation and toxicity of amyloid-beta. The study was conducted in collaboration with Professor Seung Jae Lee's team in the Department of Chemistry at Jeonbuk National University, Dr. Chul-Ho Lee and Dr. Kyoung-Shim Kim of the Korea Research Institute of Bioscience and Biotechnology (KRIBB), Dr. Young-Ho Lee of the Korea Basic Science Institute (KBSI), and Dr. Jiyong Park of the Institute for Basic Science (IBS).

One of the hallmarks of Alzheimer's disease is the abnormal aggregation and accumulation of amyloid-beta in the brain. Toxic aggregates formed during this process can damage nerve cells. The team sought to suppress this harmful aggregation and reduce the toxicity of existing aggregates.

The team used a zinc finger protein, which is best known for its role in gene regulation. Zinc ions stabilize the protein's folded structure, enabling it to recognize DNA or RNA.

The researchers noted that the protein's surface can also bind to other biomolecules, including proteins. They therefore tested whether it could bind directly to a disease-related protein. Through computer simulations and experiments, they confirmed that ZF2–4, a specific segment of the zinc finger protein, binds directly to regions of amyloid-beta involved in its aggregation.

This binding altered the aggregation of amyloid-beta. The formation of long, entangled toxic amyloid-beta fibrils was suppressed, and aggregates that were less toxic to cells formed instead. When preformed fibrils were treated with ZF2–4, they broke down into short, thin fragments, and their toxicity to cells decreased.

The team also developed a method for delivering the protein to the brain. The brain is protected by the blood–brain barrier, which restricts the entry of harmful substances but also makes it difficult for therapeutic proteins to reach the brain. The researchers attached a short peptide to the protein to help it cross the barrier, creating a brain-penetrant variant named ZF2–4–P9.

When ZF2–4–P9 was administered to a transgenic mouse model of Alzheimer's disease, amyloid-beta deposits in the cerebral cortex and the hippocampus each decreased by about 53% compared with the control group. The hippocampus is a brain region important for memory and learning.

The treatment also reduced excessive activation of microglia, the brain's immune cells. Microglia protect the brain, but when they become overly activated, they can contribute to inflammatory responses. In mice treated with the modified protein, microglial activation decreased by about 29% in the cerebral cortex and about 50% in the hippocampus compared with the control group.

In behavioral tests, the treated mice showed improved recognition memory, which is the ability to distinguish a familiar object from a new one. However, no statistically significant improvements were observed in other memory and learning tests. Because these results were obtained in animal experiments, further studies are needed to evaluate therapeutic efficacy and long-term safety before the approach can be applied to humans.

The study shows that engineering a protein's surface and structure can help control the harmful aggregation of disease-related proteins. The findings could support the development of protein-based therapeutics that target amyloid-beta.

This study shows that zinc finger proteins, which are well known as tools for gene regulation, can bind directly to disease-causing proteins and suppress their pathological aggregation."

Mi Hee Lim, Professor, Korea Advanced Institute of Science & Technology

She added that this principle could help researchers design new protein-based therapeutics that target specific diseases.

Dr. Seongmin Park, a postdoctoral researcher at KAIST (now at KBSI), Yunha Hwang, a Ph.D. candidate at Jeonbuk National University, and Jimin Kwak, a student in the integrated master's and doctoral program at KAIST, served as co-first authors. The findings were published online on September 30, 2026, in the international journal Advanced Science.