Jungsu Kim | Mayo Clinic (original) (raw)

Papers by Jungsu Kim

Acta Neuropathologica Communications, 2020

Microglia are resident macrophages of the central nervous system, and their unique molecular sign... more Microglia are resident macrophages of the central nervous system, and their unique molecular signature is dependent upon CSF-1 signaling. Previous studies have demonstrated the importance of CSF-1R in survival and development of microglia in animal models, but the findings are of uncertain relevance to understanding the influence of CSF-1R on microglia in humans. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) [also known as adult onset leukoencephalopathy with spheroids and pigmented glia (ALSP)] is a neurodegenerative disorder primarily affecting cerebral white matter, most often caused by mutations of CSF1R. Therefore, we hypothesized that the molecular profile of microglia may be affected in HDLS. Semi-quantitative immunohistochemistry and quantitative transcriptomic profiling revealed reduced expression of IBA-1 and P2RY12 in both white and gray matter microglia of HDLS. In contrast, there was increased expression of CD68 and CD163 in microglia in affected white ma...

Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with ... more Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with the normal functions of HDAC. Given their ability to decrease Aβ levels, HDACIs are a potential treatment for Alzheimer's disease (AD). However, it is unclear how HDACIs alter Aβ levels. We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood– brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2) and investigated how they affect Aβ levels and cognition. HDACI W2 decreased Aβ40 and Aβ42 in vitro. HDACI I2 also decreased Aβ40, but not Aβ42. We systematically examined the molecular mechanisms by which HDACIs W2 and I2 can decrease Aβ levels. HDACI W2 decreased gene expression of γ-secretase components and increased the Aβ degradation enzyme Mmp2. Similarly, HDACI I2 decreased expression of β-and γ-secretase components and increased mRNA levels of Aβ degradation enzymes. HDACI W2 also significantly decreased Aβ levels and rescued learning and memory deficits in aged hAPP 3xTg AD mice. Furthermore, we found that the novel HDACI W2 decreased tau phosphorylation at Thr181, an effect previously unknown for HDACIs. Collectively, these data suggest that class II HDACls may serve as a novel therapeutic strategy for AD.

Science translational medicine, Jan 18, 2015

Apolipoprotein E (ApoE) is an important modifier of Alzheimer's disease (AD) pathogenesis, an... more Apolipoprotein E (ApoE) is an important modifier of Alzheimer's disease (AD) pathogenesis, and its abundance has been linked to the clearance of β-amyloid (Aβ) in the brain. The pathways that control the clearance of ApoE in the brain are incompletely understood. We report that Idol, an E3 ubiquitin ligase that targets the low-density lipoprotein receptor (LDLR) for degradation, is a critical determinant of brain ApoE metabolism and Aβ plaque biogenesis. Previous work has shown that Idol contributes minimally to the regulation of hepatic LDLR expression in mice. By contrast, we demonstrate that Idol is a primary physiological regulator of LDLR protein in the brain, controlling the clearance of both ApoE-containing high-density lipoprotein (HDL) particles and Aβ. We studied the consequences of loss of Idol expression in a transgenic mouse model of Aβ amyloidosis. Idol deficiency increased brain LDLR, decreased ApoE, decreased soluble and insoluble Aβ, reduced amyloid plaque burde...

Human molecular genetics, Jan 10, 2015

Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) is one of protein glycosylations aff... more Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) is one of protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative diseases such as AlzheimerÕs disease (AD) is poorly understood. Mitochondrial ATP synthase is multiprotein complex that synthesizes ATP from ADP and Pi. Here, we found that ATP synthase subunit α (ATP5A) was O-GlcNAcylated at Thr432 and ATP5A O-GlcNAcylation was decreased in the brains of AD patients and transgenic mouse model, as well as Aβ-treated cells. Indeed, Aβ bound to ATP synthase directly and reduced the O-GlcNAcylation of ATP5A by inhibition of direct interaction between ATP5A and mitochondrial O-GlcNAc transferase, resulting in decreased ATP production and ATPase activity. Furthermore, treatment of O-GlcNAcase inhibitor rescued the Aβ-induced impairment in ATP production and ATPase activity. These results indicate that Aβ-mediated reduction of ATP synthase activity in AD pathology re...

Molecular Neurodegeneration, 2012

Background: Abnormal proteostasis due to alterations in protein turnover has been postulated to p... more Background: Abnormal proteostasis due to alterations in protein turnover has been postulated to play a central role in several neurodegenerative diseases. Therefore, the development of techniques to quantify protein turnover in the brain is critical for understanding the pathogenic mechanisms of these diseases. We have developed a bolus stable isotope-labeling kinetics (SILK) technique coupled with multiple reaction monitoring mass spectrometry to measure the clearance of proteins in the mouse brain.

Arteriosclerosis, Thrombosis, and Vascular Biology, 1991

The atherosclerotic lesion is characterized by the presence of cholesterol-loaded foam cells. Chi... more The atherosclerotic lesion is characterized by the presence of cholesterol-loaded foam cells. Chinese hamster ovary (CHO) cells do not normally store cholesteryl esters because low density lipoprotein (LDL) receptors are suppressed by exposure of these cells to LDL cholesterol. We transfected LDL receptor cDNA linked to the simian virus 40 early promoter into CHO cells (CHO 29) and found that LDL receptor binding in these cells was not suppressed by an excess amount of LDL cholesterol, indicating no regulation of the LDL receptor in CHO 29 cells. Furthermore, CHO 29 cells showed a high activity of LDL uptake and intracellular accumulation of cholesteryl esters. Light-microscopic examination demonstrated the resulting formation of foam cells in CHO 29 cells in the presence of 5 micrograms LDL/ml. These results demonstrated that foam cell changes in atherosclerotic lesions can be reproduced in CHO cells, whose LDL receptor activity is overexpressed, through the mechanism of LDL receptor-mediated endocytosis of native LDL.

PLoS ONE, 2012

Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer's disease and has been... more Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer's disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4) each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer's disease (AD). Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Ab) peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS), we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.

Journal of Clinical Investigation, 2008

APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a memb... more APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1 -/mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/ Apoe -/mice: there was significantly less amyloid β-peptide (Aβ) deposition, a redistribution of Aβ to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S-positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.

Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid ␤ precursor pro... more Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid ␤ precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer's disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-A␤1-40 transgenes in APP mouse models. Expression of BRI2-A␤1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral A␤ deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits A␤ aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of A␤ deposition in vivo.

immunoreactivity is significantly reduced in 2.5 month mice well before significant neuronal cell... more immunoreactivity is significantly reduced in 2.5 month mice well before significant neuronal cell loss is observed but where spatial reference memory displays variable deficits. Conclusion: The memory deficits in the rTg4510 mice appear to result from changes in neuronal function rather than overall neuronal death. Initial results suggest that synaptic degeneration pre-dates neuronal loss by several months. We therefore hypothesize that memory deficits in rTg4510 mice may be due at least in part to a synaptic disorder that is reversible upon suppression of mutant tau.

Neurobiology of Aging, 2004

Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles as well ... more Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles as well as progressive neuronal degeneration. Missense mutations in the APP gene, which can influence the A~ cleavage and lead to a higher aggregation potential are related to Familial Alzheimer's disease (AD). For the present study we established a new transgenic mouse model on a pure C57BL/6 background bearing human (h) APP751 (amyloid precursor protein 751) containing the London (V7t7I), the Swedish (K670M/N671L) and the Arctic (E693G) mutations under the regulatory control of the tissue-specific murine (m) Thy-1 promoter (mThy-l-hAPP751). Our data show high expression of the transgene on mRNA as well as on protein levels. Western blot analysis indicates an APP processing which is different compared to a mouse model carrying the London and the Swedish mutation alone. Cognitive abilities of two lines (TLSA14 and TLSA26) were tested in the Morris water maze with an age of 7 and 15 months. Results show severe deficits in learning and memory already with an age of 7 months and impairments were even pronounced with 15 months. First immunohistochemical investigations with the hA[3-specific antibody 6El0 show clear [3-amyloid pathology in the frontal cortex and in the hippocampus. The study will be continued with extensive analyses including neuronal cell death, evaluation of APP processing and generation of Af3-fragments and cytoskeletal changes (neurofilament, tan, MAP2). The first results indicate that we generated a valid model for neurodegeneration and therefore a new seminal AD mouse model. Background: Tan gene mutations cause frontotemporal dementia and parkinsonism linked to chromosome-17 (FTDP-17) in humans. Although tauopathy is one of the major consequences of such mutations, the relationship between behavioral and neuropathological changes in vivo have been elusive. Objective(s): Early behavioral changes were investigated in a mouse model of FTDP-17. Methods: We generated transgeuic (Tg) mice expressing modest levels of the longest human tan isoform with or without one of FTDP-17 tau gene mutations (R406W) under the control of c~-CaMKII promoter. This mutation generally causes Alzheimer-type dementia and tauopathy in humans. We have studied these mice (3 ~ 21 month-old) behaviorally (forced swim test, fear conditioning test, etc.), electrophysiologically (LTP), and neuropathologically. Results: Exogenous human tan was expressed mostly in axons of postnatal forebrain neurons in Tg brains. R406W but not wild-type (WT) tan Tg mice exhibited significant behavioral changes associated with emotion, fear and memory even when they were young (as early as 7 month of age). Male mice exhibited earlier onset of these abnormalities. Such abnormalities appear to be functional because no apparent neuropathological change was found in these young mice. Conclusions: We found that axonal expression of modest levels of mutant human tau in mice causes functional behavioral abnormalities in mice. This finding may provide insight into the early diagnosis and prevention of the disease.

Frontiers in Oncology, 2014

have contributed equally to this work.

Journal of Alzheimer's disease : JAD, Jan 26, 2015

While early-onset familial Alzheimer's disease (AD) is caused by a genetic mutation, the vast... more While early-onset familial Alzheimer's disease (AD) is caused by a genetic mutation, the vast majority of late-onset AD is likely caused by the combination of genetic and environmental factors. Unlike genetic studies, potential environmental factors affecting AD pathogenesis have not yet been thoroughly investigated. Among environmental factors, pesticides seem to be one of critical environmental contributors to late-onset AD. Recent studies reported that the serum and brains of AD patients have dramatically higher levels of a metabolite of dichlorodiphenyltrichloroethane (DDT). While these epidemiological studies provided initial clues to the environmental risks potentially contributing to disease pathogenesis, a functional approach is required to determine whether they actually have a causal role in disease development. In our study, we addressed this critical knowledge gap by investigating possible mechanisms by which DDT affects amyloid-β (Aβ) levels. We treated H4-AβPPswe o...

Molecules and Cells, 2014

Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39... more Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) is clinically characterized with progressive memory loss and cognitive decline. Synaptic dysfunction is an early pathological feature that occurs prior to neurodegeneration and memory dysfunction. Mounting evidence suggests that aggregation of amyloid-β (Aβ) and hyperphosphorylated tau leads to synaptic deficits and neurodegeneration, thereby to memory loss. Among the established genetic risk factors for AD, the ɛ4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor. We and others previously demonstrated that apoE regulates Aβ aggregation and clearance in an isoform-dependent manner. While the effect of apoE on Aβ may explain how apoE isoforms differentially affect AD pathogenesis, there are also other underexplored pathogenic mechanisms. They include differential effects of apoE on cerebral energy metabolism, neuroinflammation, neurovascular function, neurogenesis, and synaptic plasticity. ApoE is a major carrier of cholesterols that are required for neuronal activity and injury repair in the brain. Although there are a few conflicting findings and the underlying mechanism is still unclear, several lines of studies demonstrated that apoE4 leads to synaptic deficits and impairment in long-term potentiation, memory and cognition. In this review, we summarize current understanding of apoE function in the brain, with a particular emphasis on its role in synaptic plasticity and the underlying cellular and molecular mechanisms, involving low-density lipoprotein receptor-related protein 1 (LRP1), syndecan, and LRP8/ApoER2.

Experimental & molecular medicine, 2015

Nature communications, 2015

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition,... more Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT a...

Alzheimer's & Dementia, 2012

Current Enzyme Inhibition, 2013