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KAIST Proposes a New Dementia Treatment Strategy by Repositioning Molecules without Changing Their Chemical Composition <(Back row, from left) Professor Mi Hee Lim, Professor Mingeun Kim, Student Jimin Lee, Student Chanju Na, (Upper Right) Dr. Chul-Ho Lee, Dr Kyoung-Shim Kim> Conventional treatments of Alzheimer’s disease, one of the most common forms of dementia, have been largely focused on targeting individual pathological features. However, Alzheimer’s disease is a multifactorial disorder driven by multiple, tightly interconnected processes, rendering single-target therapeutic approaches inherently limited. Addressing this challenge, KAIST researchers propose a new strategy that enables the simultaneous regulation of multiple disease-inducing factors simply by rearranging the structural positions of drug candidate molecules without altering their chemical substituents. KAIST (President Kwang Hyung Lee) announced on January 22 that a research team led by Professor Mi Hee Lim of the Department of Chemistry, in collaboration with Professor Mingeun Kim of Chonnam National University, Dr. Chul-Ho Lee of the Korea Research Institute of Bioscience and Biotechnology (KRIBB), and Dr. Kyoung-Shim Kim of the Laboratory Animal Resource Center, has elucidated at the molecular level how subtle differences in molecular arrangement, specifically positional isomerism, give rise to distinct modes of action against Alzheimer’s disease. Using an Alzheimer’s disease mouse model (APP/PS1) harboring human dementia-associated genes, the research team demonstrated that these compounds also exert distinct therapeutic effects in vivo. Alzheimer’s disease does not arise from a single cause. Rather, multiple pathological factors, including amyloid-b, metal ions, and reactive oxygen species, interact synergistically to exacerbate disease progression. In particular, metal ions bind to amyloid-b, modulating its aggregation and toxicity while promoting the generation of reactive oxygen species, which in turn accelerates neuronal damage. Effective control of Alzheimer’s disease therefore requires therapeutic strategies capable of simultaneously targeting multiple interrelated pathological processes. < Alzheimer’s Disease – Chemical Approach Illustration (AI-generated image) > The researchers focused on positional isomers, molecules composed of the same chemical elements but differing only in the positions at which those elements are connected. Remarkably, simple changes in molecular positioning resulted in pronounced differences in reactivity towards reactive oxygen species, as well as in interactions with amyloid-b and metal-bound amyloid-b. To investigate these effects, the team compared the reactivities of three structurally similar molecules differing only in the positions of their functional groups. Their analyses revealed that even minimal structural rearrangements led to significant differences in antioxidant capacity and produced distinct modes of modulation of amyloid-b and metal-bound amyloid-b through different mechanisms, inducing peptide chemical modifications. In other words, the study demonstrated that Alzheimer’s disease-related pathological factors can be regulated through mechanistically distinct pathways simply by altering molecular arrangement, without changing molecular composition. Notably, a specific positional isomer capable of simultaneously modulating reactive oxygen species, amyloid-b, and metal-bound amyloid-b complexes also demonstrated therapeutic efficacy in an Alzheimer’s disease mouse model. In these experiments, the compound reduced oxidative stress in the hippocampus, the brain region critical for memory, and decreased amyloid plaque accumulation, resulting in significant improvements in memory deficits and cognitive impairment. < In Vivo Efficacy Evaluation and Biological Outcomes According to Positional Isomers of Small-Molecule Compounds > Professor Mi Hee Lim of KAIST stated, “This study demonstrates that multiple pathological factors associated with Alzheimer’s disease can be targeted simultaneously simply by adjusting molecular positioning, without altering the molecule’s core chemical framework.” She added, “These findings point to a new therapeutic strategy that may enable more precise control of complex, multifactorial diseases such as Alzheimer’s disease.” This research was conducted with Chanju Na and Jimin Lee, integrated master’s-doctoral students in the Department of Chemistry at KAIST, who served as co-first authors. The results were published in the Journal of the American Chemical Society (Impact Factor: 15.7, top 5.0% in Chemistry) in Issue 1 dated January 14, 2026. ※ Paper title: “Positional Isomerism Tunes Molecular Reactivities and Mechanisms toward Pathological Targets in Dementia” ※ DOI: 10.1021/jacs.5c14323 This study was supported by the National Research Foundation (NRF) of Korea through the Basic Research Program (Creative Research Initiative and Global Science Research Center), the NRF Sejong Science Fellowship, the NRF Ph.D. Followship, and KRIBB Institutional Funding.
2026.01.26 View 512
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 3612
KAIST to Collaborate with AT&C to Take Dominance over Dementia < Photo 1. (From left) KAIST Dean of the College of Natural Sciences Daesoo Kim, KAIST President Kwang Hyung Lee, AT&C Chairman Ki Tae Lee, AT&C CEO Jong-won Lee > KAIST (President Kwang Hyung Lee) announced on January 9th that it signed a memorandum of understanding for a comprehensive mutual cooperation with AT&C (CEO Jong-won Lee) at its Seoul Dogok Campus to expand research investment and industry-academia cooperation in preparation for the future cutting-edge digital bio era. Senile dementia is a rapidly increasing brain disease that affects 10% of the elderly population aged 65 and older, and approximately 38% of those aged 85 and older suffer from dementia. Alzheimer's disease is the most common dementia in the elderly and its prevalence has been increasing rapidly in the population of over 40 years of age. However, an effective treatment is yet to be found. The Korean government is investing a total of KRW 1.1 trillion in dementia R&D projects from 2020 to 2029, with the goal of reducing the rate of increase of dementia patients by 50%. Since it takes a lot of time and money to develop effective and affordable medicinal dementia treatments, it is urgent to work on the development of digital treatments for dementia that can be applied more quickly. AT&C, a digital healthcare company, has already received approval from the Ministry of Food and Drug Safety (MFDS) for its device for antidepressant treatment based on transcranial magnetic stimulation (TMS) using magnetic fields and is selling it domestically and internationally. In addition, it has developed the first Alzheimer's dementia treatment device in Korea and received MFDS approval for clinical trials. After passing phase 1 to evaluate safety and phase 2 to test efficacy on some patients, it is currently conducting phase 3 clinical trials to test efficacy on a larger group of patients. This dementia treatment device is equipped with a system that combines non-invasive electronic stimulations (TMS electromagnetic stimulator) and digital therapeutic prescription (cognitive learning programs) to provide precise, automated treatment by applying AI image analysis and robotics technology. Through this agreement, KAIST and AT&C have agreed to cooperate with each other in the development of innovative digital treatment equipment for brain diseases. Through research collaboration with KAIST, AT&C will be able to develop technology that can be widely applied to Parkinson's disease, stroke, mild cognitive impairment, sleep disorders, etc., and will develop portable equipment that can improve brain function and prevent dementia at home by utilizing KAIST's wearable technology. To this end, AT&C plans to establish a digital healthcare research center at KAIST by supporting research personnel and research expenses worth approximately 3 billion won with the goal of developing cutting-edge digital equipment within 3 years. The digital equipment market is expected to grow at a compounded annual growth rate of 22.1% from 2023 to 2033, reaching a market size of $1.9209 trillion by 2033. < Photo 2. (From left) Dean of the KAIST College of Natural Sciences Daesoo Kim, Professor Young-joon Lee, Professor Minee Choi of the KAIST Department of Brain and Cognitive Sciences, KAIST President Kwang Hyung Lee, Chairman Ki Tae Lee, CEO Jong-won Lee, and Headquarters Director Ki-yong Na of AT&C > CEO Jong-won Lee said, “AT&C is playing a leading role in the treatment of Alzheimer’s disease using TMS (transcranial magnetic stimulation) technology. Through this agreement with KAIST, we will do our best to create a new paradigm for brain disease treatment and become a platform company that can lead future medical devices and medical technology.” Former Samsung Electronics Vice Chairman Ki Tae Lee, a strong supporter of this R&D project, said, “Through this agreement with KAIST, we plan to prepare for a new future by combining the technologies AT&C has developed so far with KAIST’s innovative and differentiated technologies.” KAIST President Kwang Hyung Lee emphasized, “Through this collaboration, KAIST expects to build a world-class digital therapeutics infrastructure for treating brain diseases and contribute greatly to further strengthening Korea’s competitiveness in the biomedical field.” The signing ceremony was attended by KAIST President Kwang Hyung Lee, the Dean of KAIST College of Natural Sciences Daesoo Kim, AT&C CEO Lee Jong-won, and the current Chairman of AT&C, Ki Tae Lee, former Vice Chairman of Samsung Electronics.
2025.01.09 View 10013
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 23349