Biology subjects

Yoon, S. Y.

Publications and source records attributed to Yoon, S. Y..

11 recordsLinked to original sources

bioRxiv2025

Tri-AD: Hippocampal cell-type-specific responses to age, sex and APOE genotype

Alzheimers disease (AD) risk is strongly shaped by age, sex, and the apolipoprotein E {varepsilon}4 (APOE4) allele--the strongest genetic risk factor for late-onset AD. While each factor has been studied independently, their combined impact on cellular and molecular processes remains unclear. Here, we used single-nucleus RNA sequencing (snRNA-seq) to profile hippocampal cell states in a sex-balanced cohort of human APOE4/4 and APOE3/3 knock-in mice across 6, 12, and 18 months of age. We identify sex as the major driver of variation in cell-type abundance and find that oligodendrocytes exhibit pronounced male-biased transcriptional sensitivity to APOE4. Differential expression and cell-cell communication analyses further reveal sex-divergent temporal trajectories in inhibitory neurons, with females showing early APOE4-associated suppression of synaptic pathways and males displaying a delayed but convergent decline. Together, these findings clarify how age, sex, and APOE genotype jointly regulate cell-type-specific gene expression and intercellular communication in the aging hippocampus, providing an innovative and publicly accessible database for aging and AD research and related precision medicine.

bioinformatics↗

bioRxiv2024

Data-driven discovery of cell-type-directed network-correcting combination therapy for Alzheimer's disease

Alzheimers disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model, this combination therapy significantly improved memory function and reduced AD-related pathologies compared to vehicle and single-drug treatments. Single-nuclei transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/627436v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1e67fd5org.highwire.dtl.DTLVardef@1d2b779org.highwire.dtl.DTLVardef@10b6efforg.highwire.dtl.DTLVardef@1a44394_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2023

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimers Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of A{beta} and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis. HIGHLIGHTSO_LITransplanted human APOE4 neurons generate A{beta} and p-tau aggregates in APOE4-KI mouse hippocampus. C_LIO_LIHuman neuronal APOE4 promotes the formation of dense-core A{beta} plaques and p-tau aggregates. C_LIO_LIMicroglia is required for human neuronal APOE4-driven formation of p-tau aggregates. C_LIO_LIscRNA-seq reveals enrichment of MHC-II microglia in mice with human APOE4 neuron transplants. C_LI

neuroscience↗

bioRxiv2023

Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression

The full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimers disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific network hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network hyperexcitability in young E4-KI mice was mediated by hippocampal region-specific subpopulations of smaller and hyperexcitable neurons that were eliminated by selective removal of neuronal APOE4. Aged E4-KI mice exhibited hyperexcitable granule cells, a progressive inhibitory deficit, and E/I imbalance in the dentate gyrus, exacerbating hippocampal hyperexcitability. Single-nucleus RNA-sequencing revealed neuronal cell type-specific and age-dependent transcriptomic changes, including Nell2 overexpression in E4-KI mice. Reducing Nell2 expression in specific neuronal types of E4-KI mice with CRISPRi rescued their abnormal excitability phenotypes, implicating Nell2 overexpression as a cause of APOE4-induced hyperexcitability. These findings highlight the early transcriptomic and electrophysiological alterations underlying APOE4-induced hippocampal network dysfunction and its contribution to AD pathogenesis with aging.

neuroscience↗

bioRxiv2022

Fractions strategy differences in those born extremely preterm

IntroductionTo investigate the effects of different strategies and cognitive load we explored brain hemodynamic responses associated with the use of different strategies to solve subtraction of fractions. We focused on those born extremely preterm (EPT; <28 weeks gestation) as they are known to have cognitive challenges and struggle with mathematics. We also included a group of full-term (FT) peers for comparison. MethodsFunctional MRI was acquired while the participants mentally solved fraction equations using either a strategy based on improper or mixed fractions. Different fraction item types were given, which affected respective required cognitive loads per strategy. Diffusion and T1-weighted structural images were also acquired. ResultsThe EPT and FT groups differed in terms of task-related hemodynamic responses. Functional group differences were greatest when strategies were applied to item types that result in high cognitive load. Other findings showed reduced white and grey matter volume and reduced white matter connectivity in widespread areas in the EPT group compared to the FT group. ConclusionThe understanding of function and structure presented here may help inform pedagogical practices by allowing for tailoring of mathematical education through identifying suitable strategy adoption that depends on item type, to circumvent weaknesses in cognitive skills.

neuroscience↗

bioRxiv2022

Early and lifelong effects of APOE4 on neuronal gene expression networks relevant to Alzheimer's disease

Apolipoprotein E4 (APOE4) genotype and aging are critical risk factors for Alzheimers disease (AD). Aged APOE4 knock-in (APOE4-KI) mice have phenotypes reflecting features of AD. We conducted a large-scale single nucleus RNA-sequencing study to identify cell-type-specific effects of APOE4 on hippocampal gene expression during aging. APOE4-KI mice showed prominent alterations, relative to APOE3-KI mice, in neuronal transcriptome related to synaptic function, calcium signaling, and MAPK/Rap1/Pld signal transduction, starting by 5 months and persisting during aging. Mice with the APOE4 gene removed specifically from neurons failed to show most of these neuronal transcriptomic changes, suggesting a specific effect of neuron-derived APOE4 on the transcriptome. APOE4 affects similar cellular pathways in induced pluripotent stem cell-derived human neurons transplanted into APOE4-KI mouse hippocampus and in cortical neurons from aged human brains. Thus, neuronal APOE4 has early and persistent effects on neuronal transcriptomes, suggesting the requirement of early interventions for successfully treating APOE4-related AD.

neuroscience↗

bioRxiv2022

Phylogenetic analysis of human parainfluenza type 3 virus strains responsible for the outbreak during the COVID-19 pandemic in Seoul, South Korea

BackgroundHuman parainfluenza virus 3 (HPIV3) is a major respiratory pathogen that causes acute respiratory infections in infants and children. Since September 2021, an out-of-season HPIV3 rebound has been noted in Korea. The objective of this study was to analyze the molecular characteristics of the HPIV3 strains responsible for the outbreak in Seoul, South Korea. MethodsA total of 61 HPIV3-positive nasopharyngeal swab specimens were collected between October and November 2021. Using 33 HPIV3-positive specimens, partial nucleotide sequences of the HPIV3 hemagglutinin-neuraminidase (HN) gene were aligned with previously published HN gene sequences for phylogenetic and genetic distance (p-distance) analyses. ResultsPhylogenetic tree revealed that all Seoul HPIV3 strains grouped within the phylogenetic subcluster C3. However, these strains formed a unique cluster that branched separately from the C3a lineage. This cluster showed 99% bootstrap support with a p-distance < 0.001. Genetic distances within the other C3 lineages ranged from 0.013 (C3a) to 0.023 (C3c). Deduced amino acid sequences of the HN gene revealed four protein substitutions in Seoul HPIV3 strains that have rarely been observed in other reference strains: A22T, K31N, G387S, and E514K. ConclusionsPhylogenetic analysis of Seoul HPIV3 strains revealed that the strain belonged to a separate cluster within subcluster C3. Genetic distances among strains within subcluster C3 suggest the emergence of a new genetic lineage. The emergence of a new genetic lineage could pose a potential risk of a new epidemic. Further monitoring of the circulating HPIV3 strains is needed to understand the importance of newly discovered mutations.

microbiology↗

bioRxiv2021

Dentate Gyrus and CA3 GABAergic Interneurons Bidirectionally Modulate Signatures of Internal and External Drive to CA1

Specific classes of GABAergic neurons are thought to play specific roles in regulating information processing in the brain. In the hippocampus, two major classes - parvalbumin-expressing (PV+) and somatostatin-expressing (SST+) neurons - differentially regulate endogenous firing patterns and target different subcellular compartments of principal cells, but how these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesized that PV+ and SST+ interneurons in the dentate gyrus (DG) and CA3 might differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We found that while suppressing either interneuron type increased DG and CA3 output, the effects on CA1 were very different. Suppressing PV+ interneurons increased local field potential signatures of coupling from CA3 to CA1 and decreased signatures of coupling from entorhinal cortex to CA1; suppressing SST+ interneurons had the opposite effect. Thus, DG and CA3 PV+ and SST+ interneurons bidirectionally modulate the flow of information through the hippocampal circuit.

neuroscience↗

bioRxiv2020

Aβ-induced NOX2 activation underlies oxidative stress leading to brain hypometabolism and hyperactivity in Alzheimer's disease

A predominant trigger and driver of sporadic Alzheimers disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences has remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind A{beta}1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that A{beta}1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide the first direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD. Single sentence summaryBeta-amyloid induces brain hypometabolism, network hyperactivity, and behavioral changes via NADPH oxidase-mediated oxidative stress, suggesting a novel therapeutic target for Alzheimers disease treatment.

neuroscience↗

bioRxiv2019

Hepatocytic Prominin-1 protects liver fibrosis by stabilizing the SMAD7 protein

Background and AimsProminin-1 (PROM1) is known to be upregulated in hepatocytic progenitor cells (HPCs) and cholangiocytes of fibrotic livers. To understand the function of upregulated PROM1 during liver fibrosis, we analyzed liver fibrosis from global and liver-specific Prom1 knockout mice and investigated the molecular mechanism of how Prom1 protects the liver against liver fibrosis. MethodsWe analyzed PROM1 expression from human liver with mild and severe liver fibrosis (n=4-9). Liver fibrosis was induced by carbon tetrachloride (CCl4) treatment and bile duct ligation (BDL) from wild type and global and liver-specific knockout mice (n=3-13). The severity of liver fibrosis was determined by qRT-PCR, immunostaining and immunoblotting for fibrotic markers such as SMA, collagen. TGF{beta} signaling was also analyzed from fibrotic liver and primary hepatocytes of wild type and global and liver-specific knockout mice (n=3-5). Molecular interaction between PROM1 and SMAD7 was determined by endogenous and exogenous co-immunoprecipitation. ResultsPROM1 was found in the plasma membranes of both healthy and fibrotic hepatocytes and cholangiocytes. Global Prom1 knockout aggravated BDL- and CCl4-induced liver fibrosis. Prom1-/- hepatocytes showed increased TGF{beta} signaling due to reduced SMAD7 protein expression compared to that in wild-type hepatocytes. PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that liver-specific Prom 1 knockout aggravated BDL-induced liver fibrosis due to reduced levels of SMAD7. ConclusionHepatocytic PROM1 stabilizes SMAD7, preventing TGF{beta} signaling. Thus, PROM1 is necessary for the negative regulation of TGF{beta} signaling during liver fibrosis.

cell biology↗

bioRxiv2019

Early Hippocampal Sharp-Wave Ripple Deficits Predict Later Learning and Memory Impairments in an Alzheimer’s Disease Mouse Model

Alzheimers disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs) - electrophysiological signatures of memory reactivation in the hippocampus - are a compelling candidate for doing so. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knock in (apoE4-KI) mice - a model of the major genetic risk factor for AD - we found that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1-2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD.

neuroscience↗