A5011443332- Neuroinflammation and Neurodegeneration Mechanisms
- Alzheimer's disease research and treatments
- Neurological Disease Mechanisms and Treatments
- Bioinformatics and Genomic Networks
- Inflammation biomarkers and pathways
- Immune cells in cancer
- Single-cell and spatial transcriptomics
- Metabolomics and Mass Spectrometry Studies
- CRISPR and Genetic Engineering
- Plant Virus Research Studies
- Ferroptosis and cancer prognosis
- Galectins and Cancer Biology
- RNA and protein synthesis mechanisms
- Nuclear Structure and Function
- Neurogenesis and neuroplasticity mechanisms
- Signaling Pathways in Disease
- RNA modifications and cancer
- Parkinson's Disease Mechanisms and Treatments
- Phytoplasmas and Hemiptera pathogens
- Genomics and Phylogenetic Studies
- Peroxisome Proliferator-Activated Receptors
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Epigenetics and DNA Methylation
- Cerebrospinal fluid and hydrocephalus
Washington University in St. Louis
2020-2024
Hope Center for Neurological Disorders
2021-2022
Brigham Young University
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...
Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal profiles, one them showing signs poor cognitive function, a faster pace disease progression, shorter survival disease, severe neurodegeneration astrogliosis, reduced...
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...
Abstract Cotton is an important crop that has made significant gains in production over the last century. Emerging pests such as reniform nematode have threatened cotton production. The rare African diploid species Gossypium longicalyx a wild been used source of immunity. While mapping and breeding efforts some strides transferring this immunity to cultivated polyploid species, complexities interploidal transfer combined with substantial linkage drag inhibited progress area. Moreover, shares...
Different species, genes, and locations within genes use different codons to fine-tune gene expression. Within the ramp sequence assists in ribosome spacing decreases downstream collisions by incorporating slowly-translated at beginning of a gene. Although previously reported as occurring some no previous attempt extracting from specific has been published. We present ExtRamp, software package that quickly extracts sequences any species using tRNA adaptation index or relative codon...
Abstract Background Single-cell technologies have unveiled various transcriptional states in different brain cell types. Transcription factors (TFs) regulate the expression of related gene sets, thereby controlling these diverse states. Apolipoprotein E ( APOE ), a pivotal risk-modifying Alzheimer’s disease (AD), is expressed specific glial associated with AD. However, it still unknown whether upstream regulatory programs that modulate its are shared across types or to microglia and...
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 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...
<title>Abstract</title> Background Substantial evidence has established the critical role of microglia, brain's resident immune cells, in pathogenesis Alzheimer's disease (AD). Microglia exhibit diverse transcriptional states response to neuroinflammatory stimuli, and understanding these is crucial for elucidating underlying mechanisms AD. Methods In this work, we integrated single-cell spatially resolved transcriptomics data from multiple cohorts brain regions, including microglia...
Abstract Background The cerebrovasculature is an essential component of brain homeostasis. Cerebrovascular disorders are associated with increased risk for neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms by which cerebrovascular dysfunction contributes to neurodegeneration poorly understood. Method We optimized nuclei isolation from human brains increase representation cells (CVC) and performed single‐nucleus transcriptomic profiles (snRNA‐seq)...
Abstract Cotton is an important crop that has made significant gains in production over the last century. Emerging pests such as reniform nematode have threatened cotton production. The rare African diploid species Gossypium longicalyx a wild been used source of immunity. While mapping and breeding efforts some strides transferring this immunity to cultivated polyploid species, complexities interploidal transfer combined with substantial linkage drag inhibited progress area. Moreover, shares...
Abstract Background AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex architectures. We sought to investigate the glial neuronal pathways affected by at cell specific resolution. To do so, we generated unsorted brain single‐nuclei RNA‐sequence from carrier of mutation high‐risk variants associated with Knight‐ADRC DIAN banks. Methods sequenced 74 parietal lobe carriers APP , PSEN1 PSEN2 mutations (N = 19), variants, including APOE e4 26) TREM2 (...
Abstract Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in brain. AD also result complex genetic architecture that can be leveraged to understand pathways central processes. We have previously identified coding variants phospholipase D3 ( PLD3 ) gene double late-onset risk. However, mechanism which impacts risk unknown. One variant, p.A442A, disrupts a splicing enhancer-binding site reduces human brains. Using...
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 The clinical and molecular heterogeneity of Alzheimer disease (AD) is increasingly recognized as a major factor impacting diagnosis accuracy, the design therapeutic interventions trials, development effective treatments for AD. Recently, research efforts have leveraged data to characterize AD patients into subgroups. However, influence that such profiles may on cognitive decline trajectories remains poorly understood. Comprehensive studies aggregate multiple modalities...
Abstract Background DNAJC5 encodes co‐chaperone cysteine‐string protein alpha (CSPα), a synaptic and endolysosomal whose mutations cause adult‐onset neuronal ceroid lipofuscinosis (ANCL). Characterized by dysfunction, microgliosis, loss, aggregation, ANCL shares pathological features with Alzheimer’s disease (AD). The role of CSPα in non‐neuronal cell types has been understudied. Here, we aimed to address this gap hypothesized that plays yet undefined microglial AD. Method Aβ levels plaques...
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 We leveraged digital deconvolution methods to determine cellular changes from brain transcriptomics of Alzheimer’s Disease(AD), and identified a change in proportion between neuropathology, severity the disease as determined by Clinical Dementia Rating[5]. expanded these approaches Cerebral Spinal Fluid(CSF), evaluate associated with progresses. Method used RNAseq data published sources test refine gene panel deconvolve ambient RNA CSF. Candidate marker genes were...
Abstract Background There is increasing evidence indicating sex‐specific patterns in disease manifestation and sex differences the rates of cognitive decline brain atrophy. Sex‐related AD‐associated genes are starting to emerge, but these have not been systematically studied at cell‐type‐specific transcriptome‐wide expression levels. We leveraged single‐nucleus RNA‐seq (snRNA‐seq) systems biology approaches identify transcriptomic modules human brains determine associated with sex‐AD...
Abstract Background The molecular data from multiple brain regions, cohorts, experimental models are seldom integrated comprehensively, although it provides a unique opportunity to study the cellular heterogeneity and changes across AD etiology progression. We have developed new reference model bridge datasets. Method leveraged single‐nuclei transcriptomic profiles (snRNA‐seq) of human microglia (parietal cortex 67 donors Knight ADRC DIAN banks; N = 15,726; Dataset1) [1], iPSC‐MLC...
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 Alzheimer’s disease (AD) is a complex and heterogeneous trait in which multiple molecular pathways are disrupted different cell‐types culminating disease. Genetic variants TREM2, gene expressed microglia, have been associated with high‐risk AD, similarly soluble TREM2 (sTREM2) levels the cerebrospinal fluid (CSF) AD. In previous Genome‐wide association study (GWAS) of CSF sTREM2 levels, genetic variant near MS4A cluster accounted for 6 percent protein’s variance...