Single-nucleus multiome analysis of human cerebellum in Alzheimer’s disease-related dementia DOI Creative Commons
Feixiong Cheng, Yayan Feng, Margaret E. Flanagan

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 16, 2024

Abstract Although human cerebellum is known to be neuropathologically impaired in Alzheimer’s disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional epigenomic changes that contribute this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq snATAC-seq) analysis of 103,861 nuclei isolated from 9 cases AD/ADRD 8 controls, with frontal cortex 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, identified 431,834 significant linkages between gene expression subtype-specific chromatin accessibility regions enriched candidate cis-regulatory elements (cCREs). These cCREs were associated AD/ADRD-specific transcriptomic disease-related regulatory networks, especially RAR Related Orphan Receptor A (RORA) E74 Like ETS Transcription Factor 1 (ELF1) cerebellar Purkinje cells granule cells, respectively. Trajectory populations further disease-relevant transcription factors, such as RORA, their targets. Finally, prioritized two likely causal genes, including Seizure Homolog 2 (SEZ6L2) KAT8 Regulatory NSL Complex Subunit (KANSL1) through integrative derived snATAC-seq, genome-wide loci, Hi-C looping data. This first landscape here offer novel genomic insights into neuropathology pathobiology other neurological disorders if broadly applied.

Language: Английский

Emerging diagnostics and therapeutics for Alzheimer disease DOI
Wade Self, David M. Holtzman

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(9), P. 2187 - 2199

Published: Sept. 1, 2023

Language: Английский

Citations

183
Gene regulatory network inference in the era of single-cell multi-omics DOI
Pau Badia-i-Mompel, Lorna Wessels, Sophia Müller‐Dott

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(11), P. 739 - 754

Published: June 26, 2023

Language: Английский

Citations

177
Polygenic regression uncovers trait-relevant cellular contexts through pathway activation transformation of single-cell RNA sequencing data DOI Creative Commons
Yunlong Ma, Chunyu Deng, Yijun Zhou

et al.

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(9), P. 100383 - 100383

Published: Aug. 18, 2023

Advances in single-cell RNA sequencing (scRNA-seq) techniques have accelerated functional interpretation of disease-associated variants discovered from genome-wide association studies (GWASs). However, identification trait-relevant cell populations is often impeded by inherent technical noise and high sparsity scRNA-seq data. Here, we developed scPagwas, a computational approach that uncovers cellular context integrating pathway activation transformation data GWAS summary statistics. scPagwas effectively prioritizes genes, which facilitates types/populations with accuracy extensive simulated real datasets. Cellular-level results identified novel subpopulation naive CD8+ T cells related to COVID-19 severity oligodendrocyte progenitor microglia subsets critical pathways genetic influence Alzheimer's disease. Overall, our provides new insights for the discovery types improves mechanistic understanding disease perspective.

Language: Английский

Citations

48
Unraveling the intercellular communication disruption and key pathways in Alzheimer’s disease: an integrative study of single-nucleus transcriptomes and genetic association DOI Creative Commons
Andi Liu, Brisa S. Fernandes, Citu Citu

et al.

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: Jan. 2, 2024

Recently, single-nucleus RNA-seq (snRNA-seq) analyses have revealed important cellular and functional features of Alzheimer's disease (AD), a prevalent neurodegenerative disease. However, our knowledge regarding intercellular communication mediated by dysregulated ligand-receptor (LR) interactions remains very limited in AD brains.

Language: Английский

Citations

14
Gene networks and systems biology in Alzheimer's disease: Insights from multi‐omics approaches DOI Creative Commons
Negin Rahimzadeh, Shushrruth Sai Srinivasan, Jing Zhang

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(5), P. 3587 - 3605

Published: March 27, 2024

Despite numerous studies in the field of dementia and Alzheimer's disease (AD), a comprehensive understanding this devastating remains elusive. Bulk transcriptomics have provided insights into underlying genetic factors at high level. Subsequent technological advancements focused on single-cell omics, encompassing techniques such as RNA sequencing epigenomics, enabling capture transcripts chromatin states single cell or nucleus resolution. Furthermore, emergence spatial omics has allowed study gene responses vicinity amyloid beta plaques across various brain regions. With vast amount data generated, utilizing regulatory networks to comprehensively become essential. This review delves some employed AD, explores discoveries made using these techniques, provides future field.

Language: Английский

Citations

9
Multiomic profiling of transcription factor binding and function in human brain DOI
Jacob M. Loupe, Ashlyn G. Anderson, Lindsay F. Rizzardi

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(7), P. 1387 - 1399

Published: June 3, 2024

Language: Английский

Citations

9
Single cell transcriptomes and multiscale networks from persons with and without Alzheimer’s disease DOI Creative Commons
Qi Wang,

Jerry Antone,

Eric Alsop

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 10, 2024

The emergence of single nucleus RNA sequencing (snRNA-seq) offers to revolutionize the study Alzheimer's disease (AD). Integration with complementary multiomics data such as genetics, proteomics and clinical provides powerful opportunities link cell subpopulations molecular networks a broader disease-relevant context. We report snRNA-seq profiles from superior frontal gyrus samples 101 well characterized subjects Banner Brain Body Donation Program in combination whole genome sequences. findings that common AD risk variants CR1 expression oligodendrocytes alterations hematological parameters. observed an AD-associated CD83(+) microglial subtype unique which is associated immunoglobulin IgG4 production transverse colon. Our major observations were replicated two additional, independent sets. These illustrate power multi-tissue profiling contextualize brain transcriptomics reveal biology.

Language: Английский

Citations

8
Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus DOI Creative Commons

Bianca Caroline Bobotis,

Mohammadparsa Khakpour,

Olivia Braniff

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 24, 2025

The brain presents various structural and functional sex differences, for which multiple factors are attributed: genetic, epigenetic, metabolic, hormonal. While biological is determined by both chromosomes hormones, little known about how these two interact to establish this dimorphism. Sex differences in the also affect its resident immune cells, microglia, actively survey parenchyma with hormones throughout life. However, microglial density distribution, morphology ultrastructural patterns physiological conditions during adulthood largely unknown. Here, we investigated aforementioned properties of microglia using Four Core Genotypes (FCG) model, allows an independent assessment gonadal chromosomal effects four conditions: FCG XX Tg XY− (both ovaries); XXSry XYSry testes). We compared results XY wild-type (WT) mice. In adult mice, focused our investigation on ventral hippocampus across different layers: CA1 stratum radiatum (Rad) lacunosum-moleculare (LMol), as well dentate gyrus polymorphic layer (PoDG). Double immunostaining Iba1 TMEM119 revealed that influenced hormones. show Rad LMol denser however, were densest WT PoDG, ovarian animals had increased testes animals. Additionally, was modulated a complex interaction between chromosomes, affecting their cellular soma arborization hippocampal layers. Moreover, analysis showed make overall more contacts pre- post-synaptic elements than Lastly, markers stress, including mitochondrion elongation, dilation endoplasmic reticulum Golgi apparatus, mostly chromosomally driven. Overall, characterized aspects normal found be shaped shading light onto immunity at steady-state.

Language: Английский

Citations

1
Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements DOI Creative Commons
Brianne B. Rogers, Ashlyn G. Anderson,

Shelby N. Lauzon

et al.

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 111(2), P. 259 - 279

Published: Jan. 21, 2024

Language: Английский

Citations

7
Established and emerging techniques for the study of microglia: visualization, depletion, and fate mapping DOI Creative Commons

Bianca Caroline Bobotis,

Torin Halvorson, Micaël Carrier

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Feb. 15, 2024

The central nervous system (CNS) is an essential hub for neuronal communication. As a major component of the CNS, glial cells are vital in maintenance and regulation network dynamics. Research on microglia, resident innate immune has advanced considerably recent years, our understanding their diverse functions continues to grow. Microglia play critical roles formation synapses, myelination, responses injury, neurogenesis, inflammation, many other physiological processes. In parallel with advances microglial biology, cutting-edge techniques characterization properties have emerged increasing depth precision. Labeling tools reporter models important study morphology, ultrastructure, dynamics, but also isolation, which required glean key phenotypic information through single-cell transcriptomics emerging approaches. Strategies selective depletion modulation can provide novel insights into microglia-targeted treatment strategies neuropsychiatric neurodegenerative conditions, cancer, autoimmunity. Finally, fate mapping as tool answer fundamental questions about including origin, migration, proliferation throughout lifetime organism. This review aims comprehensive discussion these established techniques, applications microglia development, homeostasis, CNS pathologies.

Language: Английский

Citations

6