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KAIST-KBSI, ‘Communication’ Between Proteins Found to Mitigate Alzheimer’s Toxicity… Opening the Path to Treatment
50 million people worldwide are estimated to have dementia, with Alzheimer’s disease—accounting for over 70%—being the representative neurodegenerative brain disorder. A Korean research team has, for the first time in the world, identified at the molecular level that tau and amyloid-β, the two key pathological proteins of Alzheimer’s disease, directly communicate to regulate toxicity. This achievement is expected to provide new insights into the pathophysiology of Alzheimer’s disease, as well as important clues for discovering biomarkers for early diagnosis and developing therapeutics for neurodegenerative brain disorders.
KAIST (President Kwang Hyung Lee) announced on the 24th of August that Professor Mi Hee Lim’s research team in the Department of Chemistry (Director of the Research Center for Metal–Neuroprotein Interactions), in collaboration with Dr. Young-Ho Lee’s team from the Division of Advanced Biomedical Research at the Korea Basic Science Institute (KBSI, President Sung-kwang Yang) under the National Research Council of Science & Technology (NST, Chairperson Yeung-Shik Kim), together with Dr. Yun Kyung Kim and Dr. Sung Su Lim from the Brain Science Institute at the Korea Institute of Science and Technology (KIST, President Sang-Rok Oh), has elucidated at the molecular level that the microtubule-binding domain of tau—one of the major pathological proteins of Alzheimer’s disease—directly interacts with amyloid-β (tau–amyloid-β communication), alters its aggregation pathway, and alleviates cellular toxicity.
Pathologically, Alzheimer’s disease is characterized by the accumulation of“neurofibrillary tangles” formed by aggregates of tau, a protein responsible for transporting nutrients and signaling molecules within neurons, and “amyloid plaques (senile plaques)” formed by clusters of amyloid-β fragments—abnormally cleaved from amyloid precursor protein, which is involved in brain development, intercellular signaling, and neuronal recovery—that aggregate in and around neuronal membranes in the brain.
Although tau and amyloid-β form pathological structures in spatially separated locations, it has been suggested that they may coexist inside and outside of cells and potentially interact. However, the molecular-level understanding of how their direct interaction affects the onset and progression of the disease has not been clearly revealed until now.
The joint research team found that among the structural repeats of tau protein that bind to microtubules (the intracellular transport system) inside neurons—K18, R1–R4, PHF6*, and PHF6—specifically K18, R2, and R3 bind with amyloid-β to form ‘tau–amyloid-β heterocomplexes.’ This process is significant because amyloid-β normally assembles into highly toxic, rigid fibers (amyloid fibrils), but when certain tau regions bind, amyloid-β shifts to an aggregation pathway that produces less toxic, less rigid aggregates.
Notably, these repeat regions of tau delay the nucleation stage (the initial step of amyloid aggregation linked to disease onset) and simultaneously alter the aggregation speed and structural form of amyloid-β associated with disease progression. As a result, the toxicity caused by amyloid-β was markedly reduced in both the intracellular and extracellular environments of the brain.
In this study, the team combined precise analytical techniques—including spectroscopy, mass spectrometry, isothermal titration calorimetry, and nuclear magnetic resonance—with cell-based toxicity assays to comprehensively analyze the structural, thermodynamic, and functional properties of tau–amyloid interactions.
The findings revealed that specific regions of tau’s microtubule-binding repeats possess both hydrophilic (water-attracting) and hydrophobic (water-repelling) characteristics, and when the balance of these two properties is optimized, tau binds more effectively to amyloid-β. In other words, the intrinsic properties of tau determine its binding affinity with amyloid-β, its modulation of aggregation pathways, and its ability to regulate toxicity.
Dr. Young-Ho Lee of KBSI stated, “This research has uncovered a new molecular mechanism for the onset and progression of dementia, an intractable neurodegenerative disease. In particular, multidisciplinary convergent research focused on molecular interactions and protein aggregation is expected to play a pivotal role in clarifying not only the cross-talk between Alzheimer’s and Parkinson’s diseases but also the interconnections among various diseases such as dementia, diabetes, and cancer.”
Professor Mi Hee Lim of KAIST added, “Tau protein does not merely contribute to pathological formation, but rather, through specific microtubule-binding repeat structures, it exerts a molecular function that actively mitigates amyloid-β aggregation and toxicity. This provides a new turning point in the pathological understanding of Alzheimer’s disease. The significance of this study lies in identifying new molecular motifs that could serve as therapeutic targets not only for Alzheimer’s but also for a variety of protein aggregation-based neurodegenerative brain disorders.”
This research, with Dr. Min Geun Kim of KAIST’s Department of Chemistry as first author, was published on August 22 in the internationally renowned journal Nature Chemical Biology (Impact factor: 13.7, top 3.8% in the field of chemistry).
※ Paper Title: “Interactions with tau’s microtubule-binding repeats modulate amyloid-β aggregation and toxicity”
※ DOI: 10.1038/s41589-025-01987-0
This research was supported by the National Research Foundation of Korea’s Basic Research Program (Leader Research and Mid-career Researcher Program), the Sejong Science Fellowship, as well as KBSI and KIST.
2025.08.25 View 3272 -
KAIST Research Team Proves How a Neurotransmitter may be the Key in Controlling Alzheimer’s Toxicity
With nearly 50 million dementia patients worldwide, and Alzheimers’s disease is the most common neurodegenerative disease. Its main symptom is the impairment of general cognitive abilities, including the ability to speak or to remember. The importance of finding a cure is widely understood with increasingly aging population and the life expectancy being ever-extended. However, even the cause of the grim disease is yet to be given a clear definition.
A KAIST research team in the Department of Chemistry led by professor Mi Hee Lim took on a lead to discovered a new role for somatostatin, a protein-based neurotransmitter, in reducing the toxicity caused in the pathogenic mechanism taken towards development of Alzheimer’s disease. The study was published in the July issue of Nature Chemistry under the title, “Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β”.
According to the amyloid hypothesis, the abnormal deposition of Aβ proteins causes death of neuronal cells. While Aβ agglomerations make up most of the aged plaques through fibrosis, in recent studies, high concentrations of transitional metal were found in the plaques from Alzheimer’s patients.
This suggests a close interaction between metallic ions and Aβ, which accelerates the fibrosis of proteins. Copper in particular is a redox-activating transition metal that can produce large amounts of oxygen and cause serious oxidative stress on cell organelles. Aβ proteins and transition metals can closely interact with neurotransmitters at synapses, but the direct effects of such abnormalities on the structure and function of neurotransmitters are yet to be understood.
Figure 1. Functional shift of somatostatin (SST) by factors in the pathogenesis of Alzheimer's disease.
Figure 2. Somatostatin’s loss-of-function as neurotransmitter. a. Schematic diagram of SST auto-aggregation due to Alzheimer's pathological factors. b. SST’s aggregation by copper ions. c. Coordination-prediction structure and N-terminal folding of copper-SST. d. Inhibition of SST receptor binding specificity by metals.
In their research, Professor Lim’s team discovered that when somatostatin, the protein-based neurotransmitter, is met with copper, Aβ, and metal-Aβ complexes, self-aggregates and ceases to perform its innate function of transmitting neural signals, but begins to attenuate the toxicity and agglomeration of metal-Aβ complexes.
Figure 3. Gain-of-function of somatostatin (SST) in the dementia setting. a. Prediction of docking of SST and amyloid beta. b. SST making metal-amyloid beta aggregates into an amorphous form. c. Cytotoxic mitigation effect of SST. d. SST mitigating the interaction between amyloid beta protein with the cell membrane.
This research, by Dr. Jiyeon Han et al. from the KAIST Department of Chemistry, revealed the coordination structure between copper and somatostatin at a molecular level through which it suggested the agglomeration mechanism, and discovered the effects of somatostatin on Aβ agglomeration path depending on the presence or absence of metals. The team has further confirmed somatostatin’s receptor binding, interactions with cell membranes, and effects on cell toxicity for the first time to receive international attention.
Professor Mi Hee Lim said, “This research has great significance in having discovered a new role of neurotransmitters in the pathogenesis of Alzheimer’s disease.” “We expect this research to contribute to defining the pathogenic network of neurodegenerative diseases caused by aging, and to the development of future biomarkers and medicine,” she added.
This research was conducted jointly by Professor Seung-Hee Lee’s team of KAIST Department of Biological Sciences, Professor Kiyoung Park’s Team of KAIST Department of Chemistry, and Professor Yulong Li’s team of Peking University.
The research was funded by Basic Science Research Program of the National Research Foundation of Korea and KAIST.
For more information about the research team, visit the website: https://sites.google.com/site/miheelimlab/1-professor-mi-hee-lim.
2022.07.29 View 21828 -
Simple Molecular Reagents to Treat Alzheimer’s Disease
- Researchers report minimalistic principles for designing small molecules with multiple reactivities against dementia. -
Sometimes the most complex problems actually have very simple solutions. A group of South Korean researchers reported an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents against neurodegenerative disorders. The team developed redox-active aromatic molecular reagents with a simple structural composition that can simultaneously target and modulate various pathogenic factors in complex neurodegenerative disorders such as Alzheimer’s disease.
Alzheimer’s disease is one of the most prevalent neurodegenerative disorders, affecting one in ten people over the age of 65. Early-onset dementia also increasingly affects younger people.
A number of pathogenic elements such as reactive oxygen species, amyloid-beta, and metal ions have been suggested as potential causes of Alzheimer’s disease. Each element itself can lead to Alzheimer’s disease, but interactions between them may also aggravate the patient’s condition or interfere with the appropriate clinical care.
For example, when interacting with amyloid-beta, metal ions foster the aggregation and accumulation of amyloid-beta peptides that can induce oxidative stress and toxicity in the brain and lead to neurodegeneration.
Because these pathogenic factors of Alzheimer’s disease are intertwined, developing therapeutic agents that are capable of simultaneously regulating metal ion dyshomeostasis, amyloid-beta agglutination, and oxidative stress responses remains a key to halting the progression of the disease.
A research team led by Professor Mi Hee Lim from the Department of Chemistry at KAIST demonstrated the feasibility of structure-mechanism-based molecular design for controlling a molecule’s chemical reactivity toward the various pathological factors of Alzheimer’s disease by tuning the redox properties of the molecule.
This study, featured as the ‘ACS Editors’ Choice’ in the May 6th issue of the Journal of the American Chemical Society (JACS), was conducted in conjunction with KAIST Professor Mu-Hyun Baik’s group and Professor Joo-Young Lee’s group at the Asan Medical Center.
Professor Lim and her collaborators rationally designed and generated 10 compact aromatic molecules presenting a range of redox potentials by adjusting the electronic distribution of the phenyl, phenylene, or pyridyl moiety to impart redox-dependent reactivities against the multiple pathogenic factors in Alzheimer’s disease.
During the team’s biochemical and biophysical studies, these designed molecular reagents displayed redox-dependent reactivities against numerous desirable targets that are associated with Alzheimer’s disease such as free radicals, metal-free amyloid-beta, and metal-bound amyloid-beta.
Further mechanistic results revealed that the redox properties of these designed molecular reagents were essential for their function. The team demonstrated that these reagents engaged in oxidative reactions with metal-free and metal-bound amyloid-beta and led to chemical modifications. The products of such oxidative transformations were observed to form covalent adducts with amyloid-beta and alter its aggregation.
Moreover, the administration of the most promising candidate molecule significantly attenuated the amyloid pathology in the brains of Alzheimer’s disease transgenic mice and improved their cognitive defects.
Professor Lim said, “This strategy is straightforward, time-saving, and cost-effective, and its effect is significant. We are excited to help enable the advancement of new therapeutic agents for neurodegenerative disorders, which can improve the lives of so many patients.”
This work was supported by the National Research Foundation (NRF) of Korea, the Institute for Basic Science (IBS), and the Asan Institute for Life Sciences.
Image credit: Professor Mi Hee Lim, KAIST
Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part of the news coverage of this paper only.
Publication:
Kim, M. et al. (2020) ‘Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia.’ Journal of the American Chemical Society (JACS), Volume 142, Issue 18, pp.8183-8193. Available online at https://doi.org/10.1021/jacs.9b13100
Profile:
Mi Hee Lim
Professor
miheelim@kaist.ac.kr
http://sites.google.com/site/miheelimlab
Lim Laboratory
Department of Chemistry
KAIST
Profile:
Mu-Hyun Baik
Professor
mbaik2805@kaist.ac.kr
https://baik-laboratory.com/
Baik Laboratory
Department of Chemistry
KAIST
Profile:
Joo-Yong Lee
Professor
jlee@amc.seoul.kr
Asan Institute for Life Sciences
Asan Medical Center
(END)
2020.05.11 View 22968