Brain
(Alzheimer's Disease)
Collaborators
Associate Professor of Research
Neuroscience, Brain and Mind Research Institute
Associate Professor of Psychiatry
Washington University School of Medicine
Data analysis
Understanding selective neuronal vulnerability in neurodegenerative diseases like Alzheimer's, particularly regarding protein aggregation, is crucial. In this study, we reveal that excitatory neurons expressing Wolframin (WFS1) in the entorhinal cortex, an early affected region in AD, exhibit tau protein aggregates. WFS1 deficiency is associated with increased tau pathology and neurodegeneration, while overexpression of WFS1 mitigates these changes. WFS1 interacts with tau and influences susceptibility to tau pathology. In human AD, WFS1-high excitatory neurons show enrichment of chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes at early Braak stages. Tau transgenic mice with WFS1 deficiency display altered levels of ER stress and ALP-associated proteins, reversed by WFS1 overexpression. This work unveils WFS1's potential role in regulating tau pathology and neurodegeneration through chronic ER stress and the ALP, offering insights for developing therapeutics to protect vulnerable neurons in AD.
In this study, employing single-cell transcriptomics in wild-type and 5xFAD AD model mouse brains, we comprehensively mapped non-immune, non-neuronal cell populations. A distinctive oligodendrocyte state emerged in association with brain pathology, termed disease-associated oligodendrocytes (DOLs). Notably, DOLs manifested in a murine amyloidosis model long after plaque accumulation, and Aβ alone did not induce the DOL signature in vitro. DOLs were identified in tauopathy and various neurodegenerative and autoimmune inflammatory murine conditions, indicating a shared response to severe pathological conditions. Quantitative spatial analysis in mouse and postmortem human brain tissues revealed DOL marker-expressing oligodendrocytes enriched near Aβ plaques in the cortex, with the marker's expression correlating with cognitive decline in postmortem human brains. This study uncovers a shared oligodendrocyte signature across central nervous system pathologies, shedding light on their role in complex neurodegenerative diseases like Alzheimer's.
In this study, we leverage the 10x Genomics Visium platform alongside co-immunofluorescence staining of AD-associated pathological markers to unravel the spatial gene expression topography in the middle temporal gyrus (MTG) of individuals with early AD and age- and gender-matched controls. We identify unique marker genes for six cortical layers and the adjacent white matter, revealing distinct gene signatures and pathways associated with various AD pathology aspects. Co-expression analysis of differentially expressed genes (DEGs) between AD and controls uncovers four unique gene modules, with altered co-expression patterns in the presence of AD pathology variations. Validation of key representative DEGs associated with AD pathology in neurons, microglia, astrocytes, and oligodendrocytes using single-molecule fluorescent in situ hybridization reinforces the study's comprehensive insights into the spatial transcriptomic profile of the human MTG. This resource contributes to our understanding of the complex architecture and AD pathology in this vulnerable brain region.
Cellular crosstalk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer’s disease (AD). To discover crosstalk dysregulations in AD, we reconstructed crosstalk networks from single-nucleus transcriptional profiles from 67 clinically and neuropathologically well-characterized controls and AD brain donors. We predicted a significant role for TREM2 and additional AD risk genes mediating neuron-microglia crosstalk in AD. The gene sub-network mediating SEMA6D-TREM2 crosstalk is activated near Aβ plaques and SEMA6D-expressing cells and is disrupted in late AD stages. Using CRISPR-modified human induced pluripotent stem cell-derived microglia, we demonstrated that SEMA6D induces microglial activation in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular crosstalk networks can yield novel insights into AD biology.
Pathogenic tau accumulation contributes to neurodegeneration in Alzheimer's disease (AD). Exploring ways to enhance the aging brain's resilience to tau pathology presents novel therapeutic avenues. DAP12 (DNAX-activation protein 12), a key player in microglial immune responses, has been implicated in modulating tau pathology. Previous studies demonstrated that mice lacking DAP12 in tauopathy models exhibit elevated tau pathology but are protected from tau-induced cognitive deficits. Our current investigation reveals a novel resilience mechanism involving microglial interaction with oligodendrocytes. Despite increased tau inclusions, Dap12 deletion mitigates tau-induced brain inflammation and attenuates myelin and synapse loss. Notably, the absence of Dap12 prevents the formation of tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), spatially correlated with tau pathology in AD brains. This study underscores the crucial role of microglia-oligodendrocyte interactions in tau toxicity and identifies DAP12 signaling as a promising target for enhancing resilience in AD.
Computational Resources Development
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain and the most common form of dementia among the elderly. The single-cell RNA-sequencing (scRNA-Seq) and single-nucleus RNA-sequencing (snRNA-Seq) techniques are extremely useful for dissecting the function/dysfunction of highly heterogeneous cells in the brain at the single-cell level, and the corresponding data analyses can significantly improve our understanding of why particular cells are vulnerable in AD. We developed an integrated database named scREAD (single-cell RNA-Seq database for Alzheimer's disease), which is as far as we know the first database dedicated to the management of all the existing scRNA-Seq and snRNA-Seq data sets from the human postmortem brain tissue with AD and mouse models with AD pathology. scREAD provides comprehensive analysis results for 73 data sets from 10 brain regions, including control atlas construction, cell-type prediction, identification of differentially expressed genes, and identification of cell-type-specific regulons.
Single-cell RNA-sequencing (scRNA-seq) and single-nucleus RNA-sequencing (snRNA-seq) studies have provided remarkable insights into understanding the molecular pathogenesis of Alzheimer's disease. We recently developed scREAD, a database to provide comprehensive analyses of all the existing AD scRNA-seq and snRNA-seq data from the public domain. Here, we report protocols for using the scREAD web interface and running the backend workflow locally. Our protocols enable custom analyses of AD single-cell and single-nucleus gene expression profiles.
ssREAD, an upgrade from scREAD introduced in 2020, is a comprehensive repository for Alzheimer's Disease (AD) research. It includes over 189 datasets from 35 studies, totaling 2,572,355 cells, and curated spatial transcriptomics (ST) data from 12 studies, offering a thorough analysis suite for various research needs.
Spinal cord
(Spinal cord injury)
Collaborators
Professor and Associate Dean for Foundational Research
Department of Neuroscience
The Center for Brain and Spinal Cord Repair
Research Director, Belford Center for Spinal Cord Injury
Faculty Affiliate, Chronic Brain Injury
ELAM Fellow
Professor and Chair, Department of Neuroscience
University Distinguished Scholar
RayW. Poppleton Research Designated Chair
Executive Director, Belford Center for Spinal Cord Injury
Director, Center for Brain and Spinal Cord Repair
Faculty Affiliate, Chronic Brain Injury
Data Analysis
In response to neural injury or disease, microglia express immune factors and become activated. However, their role in traumatic spinal cord injury has been unclear. Our research uncovered that microglia actively promote endogenous repair processes crucial for spontaneous recovery from experimental spinal cord injury. Through RNA sequencing of both whole spinal tissue and individual cells, we identified novel genes and pathways controlled by microglia, shedding light on their essential role in the recovery process.
An integrated mouse spinal cord atlas revealing microglia phenotypes in health and injury conditions
Gut microbiota modifies myeloid cell's transcriptome after a spinal cord injury
Spinal cord injury and lung
Spinal cord injury and non-alcoholic steatohepatitis
Computational Resources Development
Tools
IRIS3
IRIS3: integrated cell-type-specific regulon inference server from single-cell RNA-Seq
Regulons, groups of genes controlled by a common regulator, play a pivotal role in understanding complex diseases. Identifying cell-type-specific regulons (CTSR) from single-cell RNA-Seq (scRNA-Seq) data is challenging but essential. Enter IRIS3, a groundbreaking web server for CTSR inference in human and mouse. With over 20 functionalities, IRIS3 empowers users with easy access to comprehensive interpretations and graphical visualizations of identified CTSRs. This data aids in characterizing cell types, contributing to biomedical studies by revealing major regulatory mechanisms and enabling the construction of global transcriptional regulation networks. Beyond, IRIS3 impacts complex disease investigations, regulatory network construction, and drug development.
Database
SCA
High-impact neuroinformatics labs
Research direction:
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Interpretable Deep Learning for Neuroimaging Studies
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Generative Models for Learning Underlying Geometry of Neuroimaging Data
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Identification of Digital Biomarkers for Neurological Diseases
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Joint Hypothesis- and Data-Driven Analysis
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Assistant professor at the Department of Computer Science & Engineering at Tandon School of Engineering, NYU.
Associate Professor of Psychiatry, Stanford Program
Director of Biomedical Computing, SRI International
Assistant Professor, New York
Research direction:
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The heterogeneity of structural and functional brain patterns in clinical and normative populations using novel machine learning methods and MRI and fMRI data.
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state-of-the-art electrophysiology probes to map circuit connectivity in mammalian brains and account for signal corruption and motion artifacts.
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Integrate single-cell resolution EM connectomics data with single-cell resolution genomics to discover the relationship between gene expression and circuit connectivity.
Research direction:
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Multi-Omic and Functional Genomics in Neurodegenerative Diseases
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Identification and Characterization of Cell-Specific Transposable Elements Implicated on Alzheimer's Disease and Healthy Aging
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Multimodal Characterization of the Role of Circular RNAs in Alzheimer’s Disease
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Multi-Tissue Molecular Profiling in Neurodegeneration and Aging
Professor, Washington University of Medicine
NeuroGenomics and Informatics Center Director