A5001067109- Neuroinflammation and Neurodegeneration Mechanisms
- Neurological Disease Mechanisms and Treatments
- Inflammation biomarkers and pathways
- Alzheimer's disease research and treatments
- Immune cells in cancer
- Neurogenesis and neuroplasticity mechanisms
- Retinal Development and Disorders
- Cellular Mechanics and Interactions
- Photoreceptor and optogenetics research
- Peroxisome Proliferator-Activated Receptors
- Nerve injury and regeneration
- Bioinformatics and Genomic Networks
- Photoacoustic and Ultrasonic Imaging
- RNA Research and Splicing
- S100 Proteins and Annexins
- 3D Printing in Biomedical Research
- Circadian rhythm and melatonin
- RNA regulation and disease
- Cell Adhesion Molecules Research
- Autoimmune and Inflammatory Disorders Research
- Single-cell and spatial transcriptomics
Washington University in St. Louis
2020-2024
Hope Center for Neurological Disorders
2021-2022
National Taiwan University
2016-2018
Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, cell-specific effect these is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from parietal cortex AD autosomal dominant (APP PSEN1) risk-modifying variant (APOE, TREM2 MS4A) carriers. Within individual cell types, capture commonly dysregulated across groups. specific...
Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs, with five subtypes named M1–M5) are a unique subclass of RGCs axons that project directly to many brain nuclei involved in non-image-forming functions such as circadian photoentrainment and the pupillary light reflex. Recent evidence suggests melanopsin-based signals also influence image-forming visual function, including adaptation, but mechanisms unclear. Intriguingly, small population M1 ipRGCs have...
TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation gene has been implicated risk for Alzheimer's disease and frontotemporal dementia, while homozygous mutations cause a rare leukodystrophy, Nasu-Hakola (NHD). Despite extensive investigation, role of NHD pathogenesis remains poorly understood. Here, we investigate mechanisms which stop-gain mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived (iMGLs) were generated...
Genome-wide association studies for Alzheimer disease (AD) risk have identified a number of genes enriched in microglia, including MS4A4A. Common variants MS4A4A influence AD risk, expression, TREM2 signaling, and specific microglial transcriptional state, though the exact role remains unclear. Using mouse model amyloid beta (Aβ) accumulation (5xFAD), we examined impact Ms4a4a loss on Aβ pathology. Before accumulation, reduces steady-state levels shortens half-life brain interstitial fluid....
Abstract Genome-wide association studies (GWAS) have identified many modifiers of Alzheimer disease (AD) risk enriched in microglia. Two these are common variants the MS4A locus (rs1582763: protective and rs6591561: risk) serve as major regulators CSF sTREM2 levels. To understand their functional impact on AD, we used single nucleus transcriptomics to profile brains from carriers variants. We discovered a “chemokine” microglial subpopulation that is altered variant for which MS4A4A...
Neuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across diseases, there is strong evidence for active involvement immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that tau mRNA and protein are expressed human brains induced pluripotent stem cell (iPSC)-derived (iMGLs). Using iMGLs harboring the
Abstract Background Alzheimer disease (AD) has substantial genetic, molecular, and cellular heterogeneity associated with its etiology. Much of our current understanding the main AD molecular events amyloid hypothesis ( APP, PSEN1 PSEN2 ) neuroimmune modulation TREM2 MS4A is based on genetic studies including GWAS. However, functional genes, downstream transcriptional ramifications, cell-type-specific effects many GWAS loci remain poorly understood. Understanding these can point us to...
Abstract Cellular crosstalk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis can contribute to neurodegenerative diseases such as Alzheimer’s disease (AD). To discover crosstalk dysregulations in AD, we reconstructed networks from single-nucleus transcriptional profiles 67 clinically neuropathologically well-characterized controls AD donors. We predicted a significant role TREM2 additional risk genes mediating neuron-microglia AD. The gene sub-network...
Abstract Shear wave elastography (SWE) has been widely adopted for clinical in vivo imaging of tissue elasticity disease diagnosis, and this modality can be a valuable tool vitro mechanobiology studies but its full potential yet to explored. Here we present laser speckle contrast SWE system noncontact monitoring the spatiotemporal changes extracellular matrix (ECM) stiffness three-dimensional cancer cell culture while providing submillimeter spatial resolution temporal 10 s. The shear...
Abstract Background Alzheimer disease (AD) has substantial genetic, molecular, and cellular heterogeneity associated with its etiology. However, much of the downstream cell‐type‐specific transcriptional functional ramifications familial mutations high‐risk variants for AD are still poorly understood. Methods We generated unsorted single‐nuclei transcriptomic profiles (snRNA‐seq) parietal lobes from 67 donors Knight ADRC DIAN cohorts [1] to investigate altered molecular pathways in healthy...
Abstract Background Amyloid‐beta (Aβ) plaque formation is a well‐established hallmark for Alzheimer’s disease (AD). However, the processes behind are not understood. Previous work from our group identified rare coding variants PLD3, with one variant in particular, p.A442A, disrupting splicing enhancer binding site within mRNA transcript. In this study, we present findings that PLD3 regulates Aβ clearance brain through both cell autonomous and non‐autonomous means. Method To replicate effect...
Abstract Background Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer’s disease (AD). TREM2 plays a critical role microglial activation, survival, and phagocytosis; however, the pathophysiological of sTREM2 AD is not well understood. Understanding may reveal new pathological mechanisms lead to identification therapeutic targets. We recently identified common variants membrane‐spanning 4‐domains subfamily A ( MS4A...
Abstract Background Genetics and molecular studies have implicated multiple genes, pathways, cell types in Alzheimer’s disease (AD) risk progression. How these genes pathways perturb are modulated by brain cellular crosstalk networks not been deeply characterized. Method We generated single‐nuclei transcriptomic profiles (snRNA‐seq) of parietal lobes from 67 donors the Knight ADRC DIAN banks, representing neuropathological‐free controls AD cases pre‐symptomatic AD[1]. estimated patterns...
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune by microglia in the adult brain. Homozygous loss of function TREM2 variants cause a rare leukodystrophy characterized bone cysts and early-onset dementia, Nasu-Hakola disease (NHD). However, despite intense investigation, role NHD pathogenesis remains poorly understood.Here, we investigated mechanisms which homozygous stop-gain variant (Q33X), leads to truncated transcript, contributes pathology NHD. Human induced...
Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role microglial activation, survival, and phagocytosis; however, the pathophysiological of sTREM2 AD is not well understood. Understanding may reveal new pathological mechanisms lead to identification therapeutic targets. We recently identified common variants membrane-spanning 4-domains subfamily A (MS4A) gene region that...
AD has a substantial genetic, molecular and cellular heterogeneity associated with its etiology. We sought to investigate the glial neuronal pathways affected by at cell specific resolution. To do so, we generated single-nuclei RNA-seq (snRNA-seq) from parietal cortex of Mendelian mutation carriers, sporadic neuropath-free donors Knight-ADRC Dominantly Inherited Alzheimer Network banks.We snRNAseq (10X chemistry v3) for 18 APP PSEN1 36 9 controls. After data cleaning quality control, 336,892...