Biology subjects

Tissera, S. D.

Publications and source records attributed to Tissera, S. D..

5 recordsLinked to original sources

bioRxiv2025

A Multi-omic Atlas of Human Choroid Plexus in Alzheimer's Disease

The choroid plexus (CP) regulates barrier integrity, cerebrospinal-fluid (CSF) dynamics, and immune surveillance, yet its role in Alzheimers disease (AD) remains poorly defined. We performed snRNA-seq on CP samples from 69 ROSMAP participants spanning normal cognition, mild cognitive impairment, and AD dementia, and integrated these data with spatial transcriptomics, snATAC-seq, and proteomics from CP tissue and CSF. We identified 17 CP cell states and uncovered widespread disease-associated transitions that converged into three major phenotypic axes. Along the inflammatory axis, epithelial cells and border-associated macrophages (BAMs) showed progressive immune activation, with BAMs shifting from inflammatory to stress-dominant states. In the barrier axis, epithelial cells, fibroblasts, and endothelial cells exhibited reduced junction-related gene expression and broad alterations in transport pathways. Epithelial cells also showed late-stage cilia loss and CSF-regulatory pathway impairment, indicating a breakdown in epithelial polarity and CSF sensing, consistent with abnormal CSF proteomic signatures. Along the remodeling axis, fibroblasts showed ECM alterations, while epithelial and stromal cells demonstrated aberrant cell-matrix adhesion pathways. Spatial neighborhood analysis revealed a multicellular signaling hub, with epithelial-rich niches showing the strongest dysregulation in AD. Together, these findings define a unified model of CP dysfunction in AD and position the CP as an active, multicellular contributor to AD pathophysiology.

genomics↗

bioRxiv2025

Stress-Responsive Transcriptomic Signatures in Human iPSC-Derived Microglia Reveal Links to Alzheimer's Disease Risk Genes

Commercially available human iPSC lines with inducible CRISPR interference (CRISPRi) systems offer scalable platforms for gene function studies. One widely available line, the AICS-0090 dCas9-KRAB iPSC line developed by the Allen Institute, has been extensively validated for genomic integrity and stem cell potency. However, its utility in modeling specialized immune cell types such as microglia -- and in assessing their functional responses to disease-relevant stimuli -- has not been fully established. Here, we evaluated the AICS-0090 line for its ability to differentiate into microglia-like cells, support efficient gene knockdown, and respond to environmental stressors. We assessed its differentiation capacity by qPCR, flow cytometry, and immunocytochemistry, confirming reproducible expression of microglial surface markers at early and late timepoints. Gene knockdown efficiency was validated both at the single-gene level and in pooled CRISPRi screens. Focusing on functional responsiveness, we exposed the microglia-like cells to two distinct stimuli: amyloid-{beta} (A{beta}), a disease-associated trigger in Alzheimers disease, and lipopolysaccharide (LPS), a classical inflammatory signal. Transcriptomic and functional analyses revealed stimulus-specific responses: A{beta} induced limited activation of stress and inflammation pathways, whereas LPS elicited broader transcriptional reprogramming and cytokine release. Signatures from both conditions partially overlapped with ex vivo human and mouse microglial states. Together, these findings support the use of the AICS-0090 dCas9-KRAB iPSC-derived microglia-like cells as a flexible and tractable model for gene function interrogation under defined inflammatory contexts, with potential for future applications in neuroimmune modeling and perturbation-based screening.

neuroscience↗

bioRxiv2024

Spatial Expression of Long Non-Coding RNAs in Human Brains of Alzheimer's Disease

BackgroundLong non-coding RNAs (lncRNAs) are critical regulators of physiological and pathological processes, with their dysregulation increasingly implicated in aging and Alzheimers disease (AD). To investigate the spatial and cellular distribution of lncRNAs in the aging brain, we leveraged published spatial transcriptomics (ST), single-nucleus RNA sequencing (snRNA-seq), and bulk RNA-seq datasets from the dorsolateral prefrontal cortex (DLPFC) of ROSMAP participants with and without pathological AD. ResultsLncRNAs exhibited greater subregion-specific expression than mRNAs, with enrichment in antisense and lincRNA biotypes. Subregion-enriched lncRNAs were generally not cell-type specific, and vice versa. Differential expression analysis of ST data identified AD-associated lncRNAs with distinct spatial patterns and moderate overlap with differentially expressed (DE) lncRNAs from bulk RNA-seq. Gene set enrichment revealed their involvement in chromatin remodeling, epigenetic regulation, and RNA metabolism. We also identified AD DE lncRNAs across major brain cell types using snRNA-seq but overlap with ST DE lncRNAs was limited. Among previously reported lncRNAs, OIP5-AS1 was consistently upregulated in AD in all cortical subregions. Antisense oligonucleotide (ASO) knockdown of OIP5-AS1 in iPSC-derived microglia led to upregulation of pro-inflammatory genes and downregulation of DNA replication and repair pathways. Immunoassays confirmed increased secretion of pro-inflammatory cytokines. The knockdown expression pattern was enriched for microglia-specific AD DE genes and microglia states. ConclusionsThis study provides a spatial and cellular map of lncRNAs in the aging human cortex and identifies subregion-and cell-type-enriched DE lncRNAs in AD. Our findings implicate OIP5-AS1 in microglial activation, suggesting its potential contribution to AD pathogenesis.

neuroscience↗

bioRxiv2024

Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics

Amyloid-beta (A{beta}) plaques and surrounding glial activation are prominent histopathological hallmarks of Alzheimers Disease (AD). However, it is unclear how A{beta} plaques interact with surrounding glial cells in the human brain. Here, we applied spatial transcriptomics (ST) and immunohistochemistry (IHC) for A{beta}, GFAP, and IBA1 to acquire data from 258,987 ST spots within 78 postmortem brain sections of 21 individuals. By coupling ST and adjacent-section IHC, we showed that low A{beta} spots exhibit transcriptomic profiles indicative of greater neuronal loss than high A{beta} spots, and high-glia spots present transcriptomic changes indicative of more significant inflammation and neurodegeneration. Furthermore, we observed that this ST glial response bears signatures of reported mouse gene modules of plaque-induced genes (PIG), oligodendrocyte (OLIG) response, disease-associated microglia (DAM), and disease-associated astrocytes (DAA), as well as different microglia (MG) states identified in human AD brains, indicating that multiple glial cell states arise around plaques and contribute to local immune response. We then validated the observed effects of A{beta} on cell apoptosis and plaque-surrounding glia on inflammation and synaptic loss using IHC. In addition, transcriptomic changes of iPSC-derived microglia-like cells upon short-interval A{beta} treatment mimic the ST glial response and mirror the reported activated MG states. Our results demonstrate an exacerbation of synaptic and neuronal loss in low-A{beta} or high-glia areas, indicating that microglia response to A{beta}-oligomers likely initiates glial activation in plaque-glia niches. Our study lays the groundwork for future pathology genomics studies, opening the door for investigating pathological heterogeneity and causal effects in neurodegenerative diseases.

genomics↗

bioRxiv2022

Dissecting the Human Leptomeninges at single-cell resolution

Emerging evidence shows that the meninges conduct essential immune surveillance and immune defense at the brain border, and the dysfunction of meningeal immunity contributes to aging and neurodegeneration. However, no study exists on the molecular properties of cell types within human leptomeninges. Here, we provide the first single nuclei profiling of dissected postmortem leptomeninges from aged individuals. We detect diverse cell types, including unique meningeal endothelial, mural, and fibroblast subtypes. For immune cells, we show that most T cells express CD8 and bear characteristics of tissue-resident memory T cells. We also identify distinct subtypes of border-associated macrophages (BAMs) that display differential gene expressions from microglia and express risk genes for Alzheimers Disease (AD), as nominated by genome-wide association studies (GWAS). We discover cell-type-specific differentially expressed genes in individuals with Alzheimers dementia, particularly in fibroblasts and BAMs. Indeed, when cultured, leptomeningeal cells display the signature of ex vivo AD fibroblasts upon amyloid-{beta} treatment. We further explore ligand-receptor interactions within the leptomeningeal niche and computationally infer intercellular communications in AD. Thus, our study establishes a molecular map of human leptomeningeal cell types, providing significant insight into the border immune and fibrotic responses in AD.

genomics↗