Haeng Jun Kim

Convergence Research Center for Diagnosis Treatment and Care System of Dementia

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Inhee Mook‐Jung

Seoul National University

Jong‐Chan Park

Sungkyunkwan University

Dongjoon Lee

Dankook University

Dahyun Yi

Seoul National University Hospital

Hee-Sun Choi

Korea Environment Institute

Min Soo Byun

Seoul National University

Wonik Lee

Seoul National University Children's Hospital

Sun‐Ho Han

Seoul National University

Jinhee Yang

Seoul National University

Hyunjung Choi

Chungbuk National University

Cooperative Institutions

Seoul National University

Seoul National University Hospital

New Generation University College

Kyung Hee University

Korea Advanced Institute of Science and Technology

Seoul National University Bundang Hospital

Convergence Research Center for Diagnosis Treatment and Care System of Dementia

Chungnam National University

National University College

Korea University

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Establishing the Trial Ready Registry and Dementia Platform Korea system to advance AD research in Korea

Alzheimer s & Dementia (2023)

Haeng Jun Kim Inhee Mook‐Jung Ki Woong Kim Sang Won Seo Jong‐Min Lee

Abstract Background Numerous studies on Alzheimer’s disease (AD) are being undertaken, and there is a plethora of high‐quality clinical data and resources for AD in Korea. However, because the resources and data are not thoroughly standardized, they are challenging to use. The Trial Ready Registry (TRR) and Dementia Platform Korea (DPK) technologies were developed to investigate possible AD therapy targets and biomarkers, as well as to progress the AD research field in Korea by standardizing the dementia dataset in Korea. Method To collect human‐derived materials with MCD, we designed the minimum common dataset (MCD), which includes clinical evaluations, cognitive evaluations, magnetic resonance imaging (MRI), Florbetaben (FBB)‐PET, Flutematamol (FMM)‐PET, and blood tests. Result The TRR‐DPK system is planned to enroll 3,000 participants in MCD exams, blood tests, and brain imaging by 2028. Since 2020, 942 people had been recruited for the system as of December 2022. We collected human‐derived materials such as plasma, serum, DNA, and PBMCs from participants with the purpose of distributing human‐derived materials matched to their brain imaging and clinical data. Conclusion We expect that the TRR‐DPK system will improve AD research by giving researchers access to human‐derived materials and a variety of quality‐controlled data.

10.1002/alz.079375

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Hearing loss as a risk factor for cognitive impairment and loss of synapses in the hippocampus

Behavioural Brain Research (2019)

Mun Young Chang Haeng Jun Kim Inhee Mook‐Jung Seung Ha Oh

10.1016/j.bbr.2019.112069

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Citations (26)

The clinical use of blood-test factors for Alzheimer’s disease: improving the prediction of cerebral amyloid deposition by the QPLEXTM Alz plus assay kit

Experimental & Molecular Medicine (2021)

Haeng Jun Kim Jong‐Chan Park Keum Sim Jung Jiyeong Kim Ji Sung Jang

Alzheimer's disease (AD) is the leading cause of dementia, and many studies have focused on finding effective blood biomarkers for the accurate diagnosis of this disease. Predicting cerebral amyloid deposition is considered the key for AD diagnosis because a cerebral amyloid deposition is the hallmark of AD pathogenesis. Previously, blood biomarkers were discovered to predict cerebral amyloid deposition, and further efforts have been made to increase their sensitivity and specificity. In this study, we analyzed blood-test factors (BTFs) that can be commonly measured in medical health check-ups from 149 participants with cognitively normal, 87 patients with mild cognitive impairment, and 64 patients with clinically diagnosed AD dementia with brain amyloid imaging data available. We demonstrated that four factors among regular health check-up blood tests, cortisol, triglyceride/high-density lipoprotein cholesterol ratio, alanine aminotransferase, and free triiodothyronine, showed either a significant difference by or correlation with cerebral amyloid deposition. Furthermore, we made a prediction model for Pittsburgh compound B-positron emission tomography positivity, using BTFs and the previously discovered blood biomarkers, the QPLEXTM Alz plus assay kit biomarker panel, and the area under the curve was significantly increased up to 0.845% with 69.4% sensitivity and 90.6% specificity. These results show that BTFs could be used as co-biomarkers and that a highly advanced prediction model for amyloid plaque deposition could be achieved by the combinational use of diverse biomarkers.

Pittsburgh compound B

Amyloid (mycology)

Pathogenesis

10.1038/s12276-021-00638-3

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Plexin-A4 mediates amyloid-β–induced tau pathology in Alzheimer’s disease animal model

Progress in Neurobiology (2021)

Sunwoo Chung Jinhee Yang Haeng Jun Kim Eun Mi Hwang Wonik Lee

Amyloid-β (Aβ) and tau are major pathological hallmarks of Alzheimer's disease (AD). Several studies have revealed that Aβ accelerates pathological tau transition and spreading during the disease progression, and that reducing tau can mitigate pathological features of AD. However, molecular links between Aβ and tau pathologies remain elusive. Here, we suggest a novel role for the plexin-A4 as an Aβ receptor that induces aggregated tau pathology. Plexin-A4, previously known as proteins involved in regulating axon guidance and synaptic plasticity, can bound to Aβ with co-receptor, neuropilin-2. Genetic downregulation of plexin-A4 in neurons was sufficient to prevent Aβ-induced activation of CDK5 and reduce tau hyperphosphorylation and aggregation, even in the presence of Aβ. In an AD mouse model that manifests both Aβ and tau pathologies, genetic downregulation of plexin-A4 in the hippocampus reduced tau pathology and ameliorated spatial memory impairment. Collectively, these results indicate that the plexin-A4 is capable of mediating Aβ-induced tau pathology in AD pathogenesis.

Plexin

Hyperphosphorylation

Tauopathy

Tau protein

10.1016/j.pneurobio.2021.102075

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Citations (11)

Liquid plasma as a treatment for cutaneous wound healing through regulation of redox metabolism

Cell Death and Disease (2023)

Hyeran Lee Sung Un Kang Haeng Jun Kim Eun Jong Ji Ju Hyun Yun

Abstract The skin functions as the outermost protective barrier to the internal organs and major vessels; thus, delayed regeneration from acute injury could induce serious clinical complications. For rapid recovery of skin wounds, promoting re-epithelialization of the epidermis at the initial stage of injury is essential, wherein epithelial keratinocytes act as leading cells via migration. This study applied plasma technology, which has been known to enable wound healing in the medical field. Through in vitro and in vivo experiments, the study elucidated the effect and molecular mechanism of the liquid plasma (LP) manufactured by our microwave plasma system, which was found to improve the applicability of existing gas-type plasma on skin cell migration for re-epithelialization. LP treatment promoted the cytoskeletal transformation of keratinocytes and migration owing to changes in the expression of integrin-dependent focal adhesion molecules and matrix metalloproteinases (MMPs). This study also identified the role of increased levels of intracellular reactive oxygen species (ROS) as a driving force for cell migration activation, which was regulated by changes in NADPH oxidases and mitochondrial membrane potential. In an in vivo experiment using a murine dorsal full-thickness acute skin wound model, LP treatment helped improve the re-epithelialization rate, reaffirming the activation of the underlying intracellular ROS-dependent integrin-dependent signaling molecules. These findings indicate that LP could be a valuable wound management material that can improve the regeneration potential of the skin via the activation of migration-related molecular signaling within the epithelial cell itself with plasma-driven oxidative eustress.

Epidermis (zoology)

10.1038/s41419-023-05610-9

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Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

Aging Cell (2019)

Hee-Sun Choi Haeng Jun Kim Jinhee Yang Sehyun Chae Wonik Lee

Abstract Alzheimer's disease (AD) is an age‐related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD‐504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLP APT ) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient‐derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau‐interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLP APT mice.

Interactome

Tau protein

Cognitive Decline

HDAC6

Organoid

Amyloid (mycology)

10.1111/acel.13081

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Citations (98)

Annexin A1 restores Aβ_1‐42‐induced blood–brain barrier disruption through the inhibition of RhoA‐ROCK signaling pathway

Aging Cell (2016)

Jong‐Chan Park Sung-Hoon Baik Sun‐Ho Han Hyun Jin Cho Hyunjung Choi

The blood-brain barrier (BBB) is composed of brain capillary endothelial cells and has an important role in maintaining homeostasis of the brain separating the blood from the parenchyma of the central nervous system (CNS). It is widely known that disruption of the BBB occurs in various neurodegenerative diseases, including Alzheimer's disease (AD). Annexin A1 (ANXA1), an anti-inflammatory messenger, is expressed in brain endothelial cells and regulates the BBB integrity. However, its role and mechanism for protecting BBB in AD have not been identified. We found that β-Amyloid 1-42 (Aβ42)-induced BBB disruption was rescued by human recombinant ANXA1 (hrANXA1) in the murine brain endothelial cell line bEnd.3. Also, ANXA1 was decreased in the bEnd.3 cells, the capillaries of 5XFAD mice, and the human serum of patients with AD. To find out the mechanism by which ANXA1 recovers the BBB integrity in AD, the RhoA-ROCK signaling pathway was examined in both Aβ42-treated bEnd.3 cells and the capillaries of 5XFAD mice as RhoA was activated in both cases. RhoA inhibitors alleviated Aβ42-induced BBB disruption and constitutively overexpressed RhoA-GTP (active form of RhoA) attenuated the protective effect of ANXA1. When pericytes were cocultured with bEnd.3 cells, Aβ42-induced RhoA activation of bEnd.3 cells was inhibited by the secretion of ANXA1 from pericytes. Taken together, our results suggest that ANXA1 restores Aβ42-induced BBB disruption through inhibition of RhoA-ROCK signaling pathway and we propose ANXA1 as a therapeutic reagent, protecting against the breakdown of the BBB in AD.

Annexin A5

Annexin A2

10.1111/acel.12530

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Citations (98)

Increased acetylation of Peroxiredoxin1 by HDAC6 inhibition leads to recovery of Aβ-induced impaired axonal transport

Molecular Neurodegeneration (2017)

Hee-Sun Choi Haeng Jun Kim Ji‐Soo Kim Soohyun Kim Jinhee Yang

Reduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer's disease (AD) and is recently being considered a possible therapeutic strategy. However, the restoring mechanism of HDAC6 inhibition has not been fully understood. Here, we found that an anti-oxidant protein Peroxdiredoxin1 (Prx1), a substrate of HDAC6, malfunctions in Aβ treated cells, the brains of 5xFAD AD model mice and AD patients. Malfunctioning Prx1, caused by reduced Prx1 acetylation levels, was recovered by HDAC6 inhibition. Increasing acetylation levels of Prx1 by HDAC6 inhibition recovered elevated reactive oxygen species (ROS) levels, elevated Ca2+ levels and impaired mitochondrial axonal transport, sequentially, even in the presence of Aβ. Prx1 mutant studies on the K197 site for an acetylation mimic or silencing mutation support the results showing that HDAC6 inhibitor restores Aβ-induced disruption of ROS, Ca2+ and axonal transport. Taken together, increasing acetylation of Prx1 by HDAC6 inhibition has several beneficial effects in AD pathology. Here, we present the novel mechanism by which elevated acetylation of Prx1 rescues mitochondrial axonal transport impaired by Aβ. Therefore, our results suggest that modulation of Prx1 acetylation by HDAC6 inhibition has great therapeutic potential for AD and has further therapeutic possibilities for other neurodegenerative diseases as well.

HDAC6

10.1186/s13024-017-0164-1

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Citations (65)

Multi‐Omics‐Based Autophagy‐Related Untypical Subtypes in Patients with Cerebral Amyloid Pathology

Advanced Science (2022)

Jong‐Chan Park Natalia Barahona‐Torres So‐Yeong Jang Kin Y. Mok Haeng Jun Kim

Abstract Recent multi‐omics analyses paved the way for a comprehensive understanding of pathological processes. However, only few studies have explored Alzheimer’s disease (AD) despite the possibility of biological subtypes within these patients. For this study, unsupervised classification of four datasets (genetics, miRNA transcriptomics, proteomics, and blood‐based biomarkers) using Multi‐Omics Factor Analysis+ (MOFA+), along with systems‐biological approaches following various downstream analyses are performed. New subgroups within 170 patients with cerebral amyloid pathology (Aβ+) are revealed and the features of them are identified based on the top‐rated targets constructing multi‐omics factors of both whole (M‐TPAD) and immune‐focused models (M‐IPAD). The authors explored the characteristics of subtypes and possible key‐drivers for AD pathogenesis. Further in‐depth studies showed that these subtypes are associated with longitudinal brain changes and autophagy pathways are main contributors. The significance of autophagy or clustering tendency is validated in peripheral blood mononuclear cells (PBMCs; n = 120 including 30 Aβ‐ and 90 Aβ+), induced pluripotent stem cell‐derived human brain organoids/microglia (n = 12 including 5 Aβ‐, 5 Aβ+, and CRISPR‐Cas9 apolipoprotein isogenic lines), and human brain transcriptome (n = 78). Collectively, this study provides a strategy for precision medicine therapy and drug development for AD using integrative multi‐omics analysis and network modelling.

Omics

Apolipoprotein E

Amyloid beta

10.1002/advs.202201212

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Citations (16)

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Gut (2019)

Min‐Soo Kim Yoonhee Kim Hyunjung Choi Woo Jin Kim Sumyung Park

Objective Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive. Design Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLP APT ) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis. Results Composition of the gut microbiota in ADLP APT mice differed from that of healthy wild-type (WT) mice. Besides, ADLP APT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLP APT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLP APT recipient mice. Conclusion These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLP APT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

Gliosis

Tauopathy

Pathogenesis

10.1136/gutjnl-2018-317431

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Citations (455)