Biology subjects

Yang, A. C.

Publications and source records attributed to Yang, A. C..

14 recordsLinked to original sources

bioRxiv2026

Domain-specific proteome remodeling defines mouse myelin aging

Myelin, once regarded as a static insulating structure, is now recognized as a dynamic component of the nervous system, capable of remodeling in response to experience. Its breakdown is linked to cognitive decline and neurodegenerative diseases, often preceding neuronal dysfunction. While the myelin proteome has been studied, the age- and sex-related changes it undergoes remain poorly understood. In this study, we purified myelin proteins from young, middle-aged, and aged male and female mice. Using mass spectrometry-based proteomics, we identified 4,095 unique proteins in males and 3,931 in females, with roughly 30% showing significant age-related changes in both sexes. We find an age-related increase in compact myelin structural proteins, such as MBP, MOBP, and CLDN11, and a selective vulnerability in non-compact myelin cytoskeletal proteins, such as SEPTIN2, SEPTIN8, and OPALIN. Notably, disease-associated proteins previously characterized in single-cell transcriptomics appear at the protein level in aged myelin. To firmly distinguish between proteins derived from oligodendrocytes and other cell types in vivo we labeled nascent oligodendrocyte proteins with bio-orthogonal non-canonical amino acid tagging (BONCAT). We discovered a dramatic age-related increase in lysosomal and vesicle-associated proteins, while translation and synaptic proteins decrease in myelin with age in both sexes. This dataset highlights molecular mechanisms underlying the loss of myelin integrity and function with age and provides a novel tool for studying oligodendrocyte-derived nascent proteins in vivo.

neuroscience↗

bioRxiv2026

Temporal AI model predicts drivers of cell state trajectories across human aging

Foundational AI models have recently shown promise for predicting the impact of perturbations on cell states. However, current models typically consider only one cell state at a time, limiting their ability to learn how cellular responses unfold over time, particularly across long trajectories such as diseases of aging. Here, we develop a temporal AI model, MaxToki, trained on nearly 1 trillion gene tokens including cell state trajectories across the human lifespan to generate cell states across long timelapses of human aging. MaxToki generalized to unseen trajectories through in-context learning and predicted novel age-modulating targets that were experimentally verified to influence age-related gene programs and functional decline in vivo. MaxToki represents a promising strategy for temporal modeling to accelerate the discovery of interventions for programming therapeutic cellular trajectories.

bioinformatics↗

bioRxiv2025

Multi-modal choroid plexus pathology in aging and Alzheimer's disease

Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimers disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology.

neuroscience↗

bioRxiv2025

Synaptic proteins that aggregate and degrade slower with aging accumulate in microglia

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with aging1,2. We engineered bioorthogonal tools3 which allowed us to tag the nascent neuronal proteome and study its turnover with aging, its propensity to aggregate, and its interaction with microglia. We discovered neuronal proteins degraded on average twice as slowly between 4- and 24-month-old mice with individual protein stability differing between brain regions. Further, we describe the aged neuronal aggregome encompassing 574 proteins, nearly 30% of which showed reduced degradation. The aggregome includes well-known proteins linked to disease as well as a trove of proteins previously not associated with neurodegeneration. Unexpectedly, we found 274 neuronal proteins accumulated in microglia with 65% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins were highly enriched, suggesting a cascade of events emanating from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly by the engulfment of synapses by microglia. These findings reveal the dramatic loss of neuronal proteome maintenance with aging which could be causal for age-related synapse loss and cognitive decline.

neuroscience↗

bioRxiv2024

Circulatory proteins shape microglia state and boost phagocytosis

Microglia, the brains immune cells, are highly responsive to their local environment. Given that circulatory proteins can enter the brain, we asked whether microglia are responsive to such proteins. Here, we identify a stable population of microglia specialized to take up circulatory proteins in a region-specific manner under physiological conditions; human hematopoietic stem cell-derived microglia replacing endogenous microglia in chimeric mice show similar regional specialization. Plasma-positive microglia are characterized by prominent expression of genes related to innate immunity and antigen presentation and exhibit high metabolic and phagocytic activity. This activity is dependent, in part, on microglial uptake and accumulation of circulatory Apolipoprotein AI (ApoA-I). Our findings thus identify a new model of communication between brain and periphery through specialized microglia.

neuroscience↗

bioRxiv2022

An Inducible Cre Mouse with Preferential Activity in Vascular Smooth Muscle Evades a Previously Lethal Intestinal Phenotype

All smooth muscle cell (SMC) restricted Cre mice recombine floxed alleles in vascular and visceral SMCs. We generated a new tamoxifen-inducible CreERT2 mouse, Itga8-CreERT2, and compared its activity to the widely used Myh11-CreERT2 mouse. Both CreERT2 mice showed similar activity in vascular SMCs; however, Itga8-CreERT2 displayed limited activity in visceral SMC-containing tissues (e.g., intestine). Myh11-CreERT2 (but not Itga8-CreERT2) mice displayed high levels of CreERT2 protein, tamoxifen-independent activity, and an altered transcriptome. Whereas Myh11-CreERT2-mediated knockout of Srf resulted in a lethal intestinal phenotype, loss of Srf with Itga8-CreERT2 (SrfItga8) revealed viable mice with attenuated vascular SMC contractile gene expression, but no evidence of intestinal pathology. Male and female SrfItga8 mice presented with vascular contractile incompetence; however, only male SrfItga8 mice showed systemic changes in blood pressure. These results establish the Itga8-CreERT2 mouse as an alternative to existing SMC Cre strains, including Myh11-CreERT2, where SMC gene loss results in visceral myopathies that obfuscate accurate phenotyping in vascular SMCs.

genetics↗

bioRxiv2021

A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk

The human brain vasculature is of vast medical importance: its dysfunction causes disability and death, and the specialized structure it forms--the blood-brain barrier--impedes treatment of nearly all brain disorders. Yet, no molecular atlas of the human brain vasculature exists. Here, we develop Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to profile the major human brain vascular and perivascular cell types through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 17 control and Alzheimers disease (AD) patients. We identify brain region-enriched pathways and genes divergent between humans and mice, including those involved in disease. We describe the principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum; but discover that many zonation and cell-type markers differ between species. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In AD, we observe a selective vulnerability of ECM-maintaining pericytes and gene expression patterns implicating dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 AD GWAS genes are expressed in the human brain vasculature, confirmed in situ. Vascular GWAS genes map to endothelial protein transport, adaptive immune, and ECM pathways. Many are microglia-specific in mice, suggesting an evolutionary transfer of AD risk to human vascular cells. Our work unravels the molecular basis of the human brain vasculature, informing our understanding of overall brain health, disease, and therapy.

neuroscience↗

bioRxiv2020

Differential patterns of gyral and sulcal morphological changes during normal aging process

The cerebral cortex is a highly convoluted structure with distinct morphologic features, namely the gyri and sulci, which are associated with the functional segregation or integration in the human brain. During the lifespan, the brain atrophy that is accompanied by cognitive decline is a well-accepted aging phenotype. However, the detailed patterns of cortical folding change during aging, especially the changing trajectories of gyri and sulci, which is essential to brain functioning, remain unclear. In this study, we investigated the morphology of the gyral and sulcal regions from pial and white matter surfaces using MR imaging data of 417 healthy participants across the lifespan (21-92y). To elucidate the age-related changes in the cortical pattern, we fitted cortical thickness and intrinsic curvature of gyri and sulci using the quadratic model to evaluate their trajectories during normal aging. Our findings show that comparing to gyri, the sulcal thinning is the most prominent pattern during the aging process, and the gyrification of pial and white matter surfaces were also affected differently, which implies the vulnerability of functional segregation during aging. Taken together, we propose a morphological model of aging that may provide a framework for understanding the mechanisms underlying the gray matter degeneration.

neuroscience↗

bioRxiv2020

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Though SARS-CoV-2 primarily targets the respiratory system, it is increasingly appreciated that patients may suffer neurological symptoms of varied severity1-3. However, an unbiased understanding of the molecular processes across brain cell types that could contribute to these symptoms in COVID-19 patients is still missing. Here, we profile 47,678 droplet-based single-nucleus transcriptomes from the frontal cortex and choroid plexus across 10 non-viral, 4 COVID-19, and 1 influenza patient. We complement transcriptomic data with immunohistochemical staining for the presence of SARS-CoV-2. We find that all major cortex parenchymal and choroid plexus cell types are affected transcriptionally with COVID-19. This arises, in part, from SARS-CoV-2 infection of the cortical brain vasculature, meninges, and choroid plexus, stimulating increased inflammatory signaling into the brain. In parallel, peripheral immune cells infiltrate the brain, microglia activate programs mediating the phagocytosis of live neurons, and astrocytes dysregulate genes involved in neurotransmitter homeostasis. Among neurons, layer 2/3 excitatory neurons--evolutionarily expanded in humans4--show a specific downregulation of genes encoding major SNARE and synaptic vesicle components, predicting compromised synaptic transmission. These perturbations are not observed in terminal influenza. Many COVID-19 gene expression changes are shared with those in chronic brain disorders and reside in genetic variants associated with cognitive function, schizophrenia, and depression. Our findings and public dataset provide a molecular framework and new opportunities to understand COVID-19 related neurological disease.

neuroscience↗

bioRxiv2020

Cell type-selective secretome profiling in vivo

Secreted polypeptides are a fundamental biochemical axis of intercellular and endocrine communication. However, a global understanding of composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection, and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte, and myeloid cell secretomes by direct purification of biotinylated secreted polypeptides from blood. Our secretome atlas validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types, and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by increased unconventional secretion of the cytosolic enzyme BHMT. This secretome profiling strategy enables dynamic and cell-type dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.

biochemistry↗

bioRxiv2020

Alteration of Power Law Scaling of Spontaneous Brain Activity in Schizophrenia

Nonlinear dynamical analysis has been used to quantify the complexity of brain signal at temporal scales. Power law scaling is a well-validated method in physics that has been used to describe the complex nature of a system across different time scales. In this research, we investigated the change of power-law characteristics in a large-scale resting-state fMRI data of schizophrenia (N = 200) and healthy participants (N = 200) derived from Taiwan Aging and Mental Illness cohort. Fourier transform was used to determine the power spectral density (PSD) of resting-state fMRI signal. We estimated the power law scaling of PSD of resting-state fMRI signal by determining the slope of the regression line fitting to the log-log plot of PSD. The power law scaling represents the dynamical properties of resting-state fMRI signal ranging from noisy oscillation (e.g., white noise) to complex fluctuations (e.g., slope approaches -1). Linear regression model was used to assess the statistical difference in power law scaling between schizophrenia and healthy participants. The significant differences in power law scaling were found in six brain regions. Schizophrenia patients has significantly more positive power law scaling (i.e., frequency components become more homogenous) at four brain regions: left precuneus, left medial dorsal nucleus, right inferior frontal gyrus, and right middle temporal gyrus, compared with healthy participants. Additionally, schizophrenia exhibited less positive power law scaling (i.e., frequency components are more dominant at lower frequency range) in bilateral putamen. Significant correlations of power law scaling with the severity of psychosis were found in these identified brain areas in schizophrenia. These findings suggest that schizophrenia has abnormal brain signal complexity toward random patterns, which is linked to psychotic symptoms. The power law scaling analysis may serve as a novel functional brain imaging marker for evaluating patients with mental illness.

neuroscience↗

bioRxiv2019

Engineering Phage Host-Range and Suppressing Bacterial Resistance Through Phage Tail Fiber Mutagenesis

The rapid emergence of antibiotic-resistant infections is prompting increased interest in phage-based antimicrobials. However, acquisition of resistance by bacteria is a major issue in the successful development of phage therapies. Through natural evolution and structural modeling, we identified host-range determining regions (HRDR) in the T3 phage tail fiber protein and developed a high-throughput strategy to genetically engineer these regions through site-directed mutagenesis. Inspired by antibody specificity engineering, this approach generates deep functional diversity (>107 different members), while minimizing disruptions to the overall protein structure, resulting in synthetic \"phagebodies\". We showed that mutating HRDRs yields phagebodies with altered host-ranges. Select phagebodies enable long-term suppression of bacterial growth by preventing the appearance of resistance in vitro and are functional in vivo using a mouse skin infection model. We anticipate this approach may facilitate the creation of next-generation antimicrobials that slow resistance development and could be extended to other viral scaffolds for a broad range of applications.\n\nHighlightsO_LIVastly diverse phagebody libraries containing 107 different members were created.\nC_LIO_LIStructure-informed engineering of viral tail fibers efficiently generated host-range alterations.\nC_LIO_LIPhagebodies prevented the development of bacterial resistance across long timescales in vitro and are functional in vivo.\nC_LI

synthetic biology↗

bioRxiv2019

Brain endothelial cells are exquisite sensors of age-related circulatory cues

Brain endothelial cells (BECs) are key elements of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access to circulatory factors. Recent studies have demonstrated that the circulatory environment can modulate brain aging, yet, the underlying processes remain largely unknown. Given the BBBs intermediary position, we hypothesized that BECs sense, adapt to, and relay signals between the aging blood and brain. We sequenced single endothelial cells from the hippocampus--a brain region key to learning, memory, and neurogenesis-- of healthy young and aged mice as well as post-exposure to inflammatory and age-related circulatory factors. We discovered that aged capillary BECs, compared with arterial and venous cells, exhibit the greatest transcriptional changes, upregulating innate immunity, antigen presentation, TGF-{beta} signaling and oxidative stress response pathways. Remarkably, short-term infusions of aged plasma into young mice recapitulated key aspects of this aging transcriptome, while infusions of young plasma into aged mice reversed select aging signatures, essentially rejuvenating the BBB endothelium transcriptome. We identify candidate pathways mediating blood-borne brain rejuvenation by comparing age-upregulated genes with those modulated by plasma exposure. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease.\n\nHighlightsO_LISingle-cell RNA sequencing of brain endothelial cells (BECs) reveals transcriptional segmentation into distinct arterial, capillary, and venous identities with age and experimental interventions\nC_LIO_LIChanges with age are heterogenous across vessel segments, with aged capillaries enriched in signatures of innate immunity, TGF-{beta} and VEGF signaling, hypoxia and oxidative stress\nC_LIO_LIBECs sense and respond transcriptionally to diverse circulatory cues: inflammatory, proaging, or rejuvenating\nC_LIO_LIAged plasma exposure recapitulates--and young plasma reverses--key transcriptomic signatures of normal BEC aging\nC_LIO_LIBEC response to aged and young plasma reveals cell non-autonomous mechanisms of blood-brain-barrier aging\nC_LI

neuroscience↗

bioRxiv2018

Topographic diversity of structural connectivity in schizophrenia

The neurobiological heterogeneity of schizophrenia is widely accepted, but it is unclear how mechanistic differences converge to produce the observed phenotype. Establishing a pathophysiological model that accounts for both heterogeneity and phenotypic similarity is essential to inform stratified treatment approaches. In this cross-sectional diffusion tensor imaging (DTI) study, we recruited 77 healthy controls (HC), and 71 patients with DSM-IV diagnosis of schizophrenia (SCZ), and reconstructed the structural connectivity of 90 brain regions covering entire cerebral cortex. We first confirmed the heterogeneity in structural connectivity by showing a reduced inter-individual similarity in SCZ compared with HC. Moreover, we found it was not possible to cluster patients into subgroups with shared patterns of dysconnectivity, indicating a high degree of mechanistic divergence in schizophrenia. Instead of the strength of connectivity between any particular brain regions, we investigated the diversity (or statistically, the variance) of the topographic distribution of the strength was reduced. HC had higher topographic diversity in whole brain structural connectivity compared to the patient group\n\n(P = 2 x 10-6, T = 4.96, Cohen'S d = 0.87). In 62 of the 90 brain regions, the topographic diversity was significantly reduced in patients compared to controls after FDR correction (<0.05). When topographic diversity was used as a discriminant feature for classification between patients and controls, we significantly (P = 4.29 x 10-24) improved the classification accuracy to 79.6% (sensitivity 78.3%, specificity 81.3%). This finding suggests highly individualized pattern of structural dysconnectivity underlying the heterogeneity of schizophrenia converges to a convergent common pathway as reduced topographic diversity for the clinical construct of the disease.

neuroscience↗