KAIST: "Alzheimer's Causes Can Be Controlled by Simply Altering Drug Candidate Structure"

A new approach has been proposed that can regulate the causes of Alzheimer's disease progression simply by altering the structural arrangement of drug candidate molecules.

On January 22, KAIST announced that a research team led by Professor Mihee Lim of the Department of Chemistry at KAIST, in collaboration with Professor Mingun Kim of the Department of Chemistry at Chonnam National University, Dr. Chulho Lee of the National Bio Infrastructure Project Division at the Korea Research Institute of Bioscience and Biotechnology (KRIBB), and Dr. Kyungsim Kim of the Laboratory Animal Resources Center, has elucidated at the molecular level that “even molecules with the same composition can act differently in Alzheimer's disease depending on their structural arrangement (positional isomers).”

Provided by KAIST (AI Generated)

Alzheimer's disease does not arise from a single cause. Various substances, such as amyloid-beta that accumulates in the brain, metal ions, and reactive oxygen species, interact with each other and exacerbate the disease.

In particular, metal ions bind to amyloid-beta, increasing its toxicity, and during this process, the production of reactive oxygen species rises, leading to more severe damage to brain nerve cells.

Therefore, to effectively control Alzheimer's disease, a strategy that can simultaneously address multiple causes is necessary.

However, existing treatments have shown limitations, as they target only one cause, such as amyloid-beta or reactive oxygen species, in preventing or treating the progression of Alzheimer's disease.

With this in mind, the joint research team focused on “positional isomers.” The concept is that “even molecules made from the same components can play entirely different roles depending on where the components are attached.” In fact, when the position of a molecule was altered, its reactivity to reactive oxygen species and its binding properties to amyloid-beta and metals changed significantly.

To confirm these differences, the research team compared and analyzed three molecules with different structures. As a result, they found that even very slight structural differences led to significant changes in the ability to reduce reactive oxygen species, the binding pattern with amyloid-beta, and the characteristics of interactions with metals.

This demonstrates that simply “changing the arrangement of a molecule” can simultaneously regulate the main causes of Alzheimer's disease in different ways.

(Back row from left) Professor Mihee Lim of KAIST, Professor Mingun Kim of Chonnam National University, KAIST students Jimin Lee and Chanju Na, (Top row from left) Dr. Chulho Lee and Dr. Kyungsim Kim of the Korea Research Institute of Bioscience and Biotechnology. Provided by KAIST

The joint research team also confirmed in experiments using an Alzheimer's mouse model that a compound with a specific structure could simultaneously regulate reactive oxygen species, amyloid-beta, and metal-amyloid-beta complexes.

This compound reduced neuronal damage in the hippocampus, the brain region responsible for memory, and decreased the accumulation of amyloid plaques, leading to significant improvements in impaired memory and cognitive function.

Professor Lim stated, “This study confirms that it is possible to simultaneously target multiple causes of Alzheimer's disease simply by adjusting the structural arrangement of molecules, without changing their components. Most importantly, the study demonstrates the potential for new therapeutic strategies that can more precisely control diseases with complex causes, such as Alzheimer's disease.”

Meanwhile, Chanju Na and Jimin Lee, students in the combined master’s and doctoral program in the Department of Chemistry at KAIST, participated as co-first authors in this study. The research findings (paper) were published in Issue 1 of the Journal of the American Chemical Society on January 14.