Biology subjects

Yang, H.-S.

Publications and source records attributed to Yang, H.-S..

8 recordsLinked to original sources

bioRxiv2025

Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's Disease

Plasma pTau217, an emerging Alzheimers disease (AD) biomarker, may reflect a synaptic response to {beta}-amyloid (A{beta}) plaques before cortical tangle formation, but its broader biological correlates remain unclear. We sought to identify associations between whole blood gene expression and plasma pTau217, and to determine whether APOE{varepsilon}4, sex, and neocortical A{beta}-PET modify these associations in 724 participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimers and accompanying LEARN studies (A4/LEARN, Agemean(SD)=72.2(4.6); 63%female). Of 20,621 genes tested (1,048 X-linked), none were directly associated with pTau217; one gene was moderated by APOE{varepsilon}4, 1,540 genes by A{beta}-PET, and 772 genes by both A{beta}-PET and sex. Over 100 of these significant associations were X-linked, supporting a role of the X chromosome in AD. Sex interactions were only observed in the presence of elevated A{beta}-PET. Our results underscore the complexity of molecular mechanisms that can be linked to plasma pTau217, particularly in the context of elevated A{beta}-PET.

neuroscience↗

bioRxiv2025

CNS-Tau Specific Antibodies Illuminate Disease Signatures Across Tauopathies

BackgroundAlternative splicing of the MAPT gene produces distinct tau isoforms in the central and peripheral nervous systems (CNS and PNS), yet their respective biological and pathological roles remain poorly understood. Recent studies suggest that CNS-tau may play a key role in amyloid-{beta} associated neurodegeneration in Alzheimers disease (AD), but the absence of isoform-specific tools has limited both mechanistic insight and biomarker development. We aimed to develop and validate CNS-tau-specific monoclonal antibodies and assess their utility in neuropathology and fluid-based biomarker assays across AD and primary tauopathies. MethodsWe generated six recombinant rabbit monoclonal antibodies targeting a CNS-tau-specific sequence encoded by exons 4 and 5. Specificity and affinity were evaluated via biolayer interferometry, immunoblotting, and tau-expressing HEK293 models. The lead clone, LL-T-1-1, was tested in postmortem brain sections from AD (n = 23), progressive supranuclear palsy (PSP, n = 3), and corticobasal degeneration (CBD, n = 3). A second clone, LL-T-1-5, was optimized for use in plasma assays via an ultrasensitive nanoneedle platform, LoD < 1 pg/ml. ResultsLL-T-1-1 showed nanomolar affinity for CNS-tau and no cross-reactivity with PNS-tau. It selectively labeled dystrophic neurites in AD and all hallmark tau lesions in PSP and CBD without antigen retrieval. LL-T-1-5-based plasma assays revealed CNS-tau levels significantly correlated with cognitive scores (MMSE and QDRS) and differentiated impaired from unimpaired individuals. ConclusionsCNS-tau-specific antibodies LL-T-1-1 and LL-T-1-5 provide new tools for neuropathology and fluid biomarker development across tauopathies.

neuroscience↗

bioRxiv2024

The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1

INTRODUCTIONThough recognized as a potential cause of Autosomal Dominant Alzheimers Disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared A{beta} production across all missense PSEN2 variants in the Alzforum database and, when possible, to corresponding PSEN1 variants. METHODSWe expressed 74 PSEN2 variants, 21 of which had homologous PSEN1 variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. A{beta} production was compared to age at symptom onset (AAO) and between homologous PSEN1/2 variants. RESULTSA{beta}42/40 and A{beta}37/42 ratios were associated with AAO across PSEN2 variants, strongly driven by PSEN2 variants with PSEN1 homologs. PSEN2 AAO was 18.3 years later compared to PSEN1 homologs. A{beta} ratios from PSEN1/2 homologs were highly correlated, suggesting a similar mechanism of {gamma}-secretase dysfunction. DISCUSSIONThe existence of a PSEN1 homolog and patterns of A{beta} production are important considerations in assessing the pathogenicity of previously-reported and new PSEN2 variants.

neuroscience↗

bioRxiv2024

Identification of Fibrinogen as a Plasma Protein Binding Partner for Lecanemab Biosimilar IgG: Implications for Alzheimer's Disease Therapy

ObjectiveRecombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimers disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, Lecanemab, administered as a bi-monthly infusion (typically 10mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study we investigated potential plasma protein binding interaction to lecanemab using lecanemab biosimilar. MethodsLecanemab biosimilar used in this study was based on publicly available sequences. ELISA and Western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions human plasma sample obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate binders was confirmed by Western blotting, ELISA, and surface plasmon resonance analysis. ResultsUsing a combination of equilibrium dialysis, ELISA, and Western blotting in human plasma, we first describe the presence of likely plasma protein binding partner to lecanemab biosimilar, and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta. InterpretationIn the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that plasma protein binding may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.

neuroscience↗

bioRxiv2023

Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease

Alzheimers Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brains cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-{beta} proteinopathy while the other mediated the effect of amyloid-{beta} in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.

neuroscience↗

bioRxiv2020

Multi-cellular communities are perturbed in the aging human brain and with Alzheimer's disease

The role of different cell types and their interactions in Alzheimers disease (AD) is an open question. Here we pursued it by assembling a high-resolution cellular map of the aging frontal cortex by single nucleus RNA-seq of 24 individuals with different clinicopathologic characteristics. We used the map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA-seq, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including inhibitory neuronal subtypes and oligodendroglial states. We further recovered a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia.

neuroscience↗

bioRxiv2020

Genetic Variants and Functional Pathways Associated with Resilience to Alzheimer's Disease

Approximately 30% of older adults exhibit the neuropathologic features of Alzheimers disease (AD) without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively normal in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modeling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5,108 participants from a clinical trial of AD and three longitudinal cohort studies of cognitive aging. All analyses were run across all participants and repeated restricting the sample to individuals with normal cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (p-values<2.5x10-20), and we observed novel correlations with neuropsychiatric conditions (p-values<7.9x10-4). Notably, neither resilience metric was genetically correlated with clinical AD (p-values>0.42) nor associated with APOE (p-values>0.13). In single variant analyses, we observed a genome-wide significant locus among participants with normal cognition on chromosome 18 upstream of ATP8B1 (index SNP rs2571244, MAF=0.08, p=2.3x10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; p=2x10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical AD, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

genetics↗

bioRxiv2018

Structural basis of recognition and destabilization of histone H2B ubiquitinated nucleosome by DOT1L histone H3 Lys79 methyltransferase

DOT1L is a histone H3 Lys79 methyltransferase whose activity is stimulated by histone H2B Lys120 ubiquitination, suggesting cross-talk between histone H3 methylation and H2B-ubiquitination. Here, we present cryo-EM structures of DOT1L complex with unmodified and H2B-ubiquitinated nucleosomes, showing that DOT1L recognizes H2B-ubiquitin and the H2A/H2B acidic patch through a C-terminal hydrophobic helix and an arginine anchor in DOT1L respectively. Furthermore, the structures combined with single-molecule FRET experiment show that H2B-ubiquitination enhances a non-catalytic function of DOT1L destabilizing nucleosome. These results establish the molecular basis of the cross-talk between H2B ubiquitination and H3 Lys79 methylation as well as nucleosome destabilization by DOT1L.

biophysics↗