Comparative mapping of single-cell transcriptomic landscapes in neurodegenerative diseases DOI Creative Commons
E. Keats Shwab, Zhaohui Man,

Daniel Oliveros Gingerich

et al.

Published: Dec. 18, 2024

ABSTRACT INTRODUCTION Alzheimer’s disease (AD), Dementia with Lewy bodies (DLB), and Parkinson’s (PD) represent a spectrum of neurodegenerative disorders (NDDs). Here, we performed the first direct comparison their transcriptomic landscapes. METHODS We profiled whole transcriptomes NDD cortical tissue by snRNA-seq. used computational analyses to identify common distinct differentially expressed genes (DEGs), biological pathways, vulnerable disease-driver cell subtypes, alteration in cell-to-cell interactions. RESULTS The same inhibitory neuron subtype was depleted both AD DLB. Potentially disease-driving neuronal subtypes were present PD Cell-cell communication predicted be increased but decreased DLB PD. DEGs most commonly shared across NDDs within subtypes. Overall, observed greatest divergence between PD, while exhibited an intermediate signature. DISCUSSION These results help explain clinicopathological this group provide unique insights into molecular mechanisms underlying pathogenesis NDDs.

Language: Английский

Alzheimer’s Disease: Models and Molecular Mechanisms Informing Disease and Treatments DOI Creative Commons

Kaden Nystuen,

Shannon M. McNamee,

Monica Akula

et al.

Bioengineering, Journal Year: 2024, Volume and Issue: 11(1), P. 45 - 45

Published: Jan. 1, 2024

Alzheimer’s Disease (AD) is a complex neurodegenerative disease resulting in progressive loss of memory, language and motor abilities caused by cortical hippocampal degeneration. This review captures the landscape understanding AD pathology, diagnostics, current therapies. Two major mechanisms direct pathology: (1) accumulation amyloid β (Aβ) plaque (2) tau-derived neurofibrillary tangles (NFT). The most common variants Aβ pathway APP, PSEN1, PSEN2 are largely responsible for early-onset (EOAD), while MAPT, APOE, TREM2 ABCA7 have modifying effect on late-onset (LOAD). More recent studies implicate chaperone proteins degrading AD. Several tests, such as cognitive function, brain imaging, cerebral spinal fluid (CSF) blood used diagnosis. Additionally, several biomarkers seem to unique specific combination expression could potentially be improved, less invasive diagnostics. In addition genetic perturbations, environmental influences, altered gut microbiome signatures, affect Effective treatments been challenging develop. Currently, there FDA approved drugs (cholinesterase inhibitors, Aß-targeting antibodies an NMDA antagonist) that mitigate rate decline symptoms distress.

Language: Английский

Citations

13
Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference DOI Creative Commons
Courtney M. Kloske, Michaël E. Belloy, Elizabeth Blue

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(9), P. 6590 - 6605

Published: July 19, 2024

Abstract INTRODUCTION The apolipoprotein E gene ( APOE ) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. influences not only amyloid‐beta and tau pathologies but also lipid energy metabolism, neuroinflammation, cerebral vascular health, sex‐dependent manifestations. Furthermore, ancestral background may significantly impact link between AD, underscoring need for more inclusive research. METHODS In 2023, Association convened multidisciplinary researchers at “AAIC Advancements: APOE” conference to discuss various topics, including their roles AD pathogenesis, progress apoE‐targeted therapeutic strategies, updates on models interventions that modulate expression function. RESULTS This manuscript presents highlights from provides overview opportunities further research field. DISCUSSION Understanding apoE's multifaceted will help develop targeted advance field precision medicine. Highlights a disease. exerts numerous effects throughout brain amyloid‐beta, tau, other pathways. AAIC encouraged discussions collaborations understanding role APOE.

Language: Английский

Citations

10
Single-nucleus multi-omics of Parkinson’s disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks DOI Creative Commons
E. Keats Shwab,

Daniel Gingerich,

Zhaohui Man

et al.

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: July 2, 2024

Abstract The genetic architecture of Parkinson’s disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression disease. Here we aimed to advance our understanding PD complexity at a subtype precision level. Using parallel single-nucleus (sn)RNA-seq snATAC-seq analyses simultaneously profiled transcriptomic chromatin accessibility landscapes temporal cortex tissues from 12 compared control subjects granular single resolution. An integrative bioinformatic pipeline was developed applied for these snMulti-omics datasets. results identified subpopulation cortical glutamatergic excitatory neurons with remarkably altered gene expression PD, including differentially-expressed genes within risk loci genome-wide association studies (GWAS). This only neuronal showing significant robust overexpression SNCA . Further characterization this neuronal-subpopulation showed upregulation specific pathways related axon guidance, neurite outgrowth post-synaptic structure, downregulated presynaptic organization calcium response. Additionally, characterized roles three molecular mechanisms governing PD-associated subtype-specific dysregulation expression: (1) changes cis-regulatory element transcriptional machinery; (2) abundance master regulators, YY1, SP3, KLF16; (3) candidate regulatory variants high linkage disequilibrium PD-GWAS genomic impacting transcription factor binding affinities. To knowledge, study first most comprehensive interrogation multi-omics landscape cell-subtype Our findings provide new insights into precise subtype, causal genes, non-coding underlying paving way development cell- gene-targeted therapeutics halt as well biomarkers early preclinical diagnosis.

Language: Английский

Citations

8
Chromatin accessibility provides a window into the genetic etiology of human brain disease DOI
Jaroslav Bendl, John F. Fullard, Kiran Girdhar

et al.

Trends in Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Integrative Epigenomic Landscape of Alzheimer's Disease Brains Reveals Oligodendrocyte Molecular Perturbations Associated with Tau DOI Open Access

Stephanie R. Oatman,

Joseph S. Reddy,

Amin Atashgaran

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract Alzheimer’s disease (AD) brains are characterized by neuropathologic and biochemical changes that highly variable across individuals. Capturing epigenetic factors associate with this variability can reveal novel biological insights into AD pathophysiology. We conducted an epigenome-wide association study of DNA methylation (DNAm) in 472 measures (Braak stage, Thal phase, cerebral amyloid angiopathy score) brain levels five proteins (APOE, amyloid-β (Aβ)40, Aβ42, tau, p-tau) core to pathogenesis. Using a regional (rCpGm) approach, we identified 5,478 significant associations, 99.7% which were tau measures. Of the tau-associated rCpGms, 93 had concordant associations external datasets comprising 1,337 samples. Integrative transcriptome-methylome analyses uncovered 535 gene expression for these rCpGms. Genes concurrent perturbations enriched oligodendrocyte marker genes, including known risk genes such as BIN1 , myelination MYRF, MBP MAG previously implicated AD, well like LDB3 . further annotated top additional 6 single cell 2 bulk transcriptome from two other tauopathies, Pick’s progressive supranuclear palsy (PSP). Our findings support consistent rCpGm tauopathies tau-related phenotypes both tissue clusters. In summary, uncover integrative epigenomic landscape demonstrate common potential pathomechanism different tauopathies.

Language: Английский

Citations

0
Personalized Single-cell Transcriptomics Reveals Molecular Diversity in Alzheimer's Disease DOI Open Access
Pramod Chandrashekar, Sayali Alatkar, Noah Cohen Kalafut

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Abstract Precision medicine for brain diseases faces many challenges, including understanding the heterogeneity of disease phenotypes. Such can be attributed to variations in cellular and molecular mechanisms across individuals. However, personalized remain elusive, especially at single-cell level. To address this, PsychAD project generated population-level single-nucleus RNA-seq data 1,494 human brains with over 6.3 million nuclei covering diverse clinical phenotypes neuropsychiatric symptoms (NPSs) Alzheimer’s (AD). Leveraging this data, we analyzed functional genomics involving cell type interactions gene regulatory networks. In particular, developed a knowledge-guided graph neural network model learn latent representations (embeddings) quantify importance scores types, genes, their each individual. Our embeddings improved phenotype classifications revealed potentially novel subtypes population trajectories AD progression, cognitive impairment, NPSs. prioritized genomic information showed significant differences level various also allowed us further identify subpopulation-level biological pathways, ancestry AD. Finally, associated genetic variants type-gene changes individuals, i.e., QTLs (grQTLs), providing insights compared existing QTLs. We validated our results using external cohorts. analyses are available through iBrainMap, an open-source computational framework, as atlas Disease.

Language: Английский

Citations

0
Application of computational algorithms for single-cell RNA-seq and ATAC-seq in neurodegenerative diseases DOI Creative Commons

Hwisoo Choi,

Hyeonkyu Kim,

Hyunhee Chung

et al.

Briefings in Functional Genomics, Journal Year: 2024, Volume and Issue: 24

Published: Nov. 5, 2024

Recent advancements in single-cell technologies, including RNA sequencing (scRNA-seq) and Assay for Transposase-Accessible Chromatin using (scATAC-seq), have greatly improved our insight into the epigenomic landscapes across various biological contexts diseases. This paper reviews key computational tools machine learning approaches that integrate scRNA-seq scATAC-seq data to facilitate alignment of transcriptomic with chromatin accessibility profiles. Applying these integrated technologies neurodegenerative diseases, such as Alzheimer's disease Parkinson's disease, reveals how changes gene expression can illuminate pathogenic mechanisms identify potential therapeutic targets. Despite facing challenges like sparsity demands, ongoing enhancements along better analytical methods, continue expand their applications. These promise revolutionize approach medical research clinical diagnostics, offering a comprehensive view cellular function pathology.

Language: Английский

Citations

0
Comparative mapping of single-cell transcriptomic landscapes in neurodegenerative diseases DOI Creative Commons
E. Keats Shwab, Zhaohui Man,

Daniel Oliveros Gingerich

et al.

Published: Dec. 18, 2024

ABSTRACT INTRODUCTION Alzheimer’s disease (AD), Dementia with Lewy bodies (DLB), and Parkinson’s (PD) represent a spectrum of neurodegenerative disorders (NDDs). Here, we performed the first direct comparison their transcriptomic landscapes. METHODS We profiled whole transcriptomes NDD cortical tissue by snRNA-seq. used computational analyses to identify common distinct differentially expressed genes (DEGs), biological pathways, vulnerable disease-driver cell subtypes, alteration in cell-to-cell interactions. RESULTS The same inhibitory neuron subtype was depleted both AD DLB. Potentially disease-driving neuronal subtypes were present PD Cell-cell communication predicted be increased but decreased DLB PD. DEGs most commonly shared across NDDs within subtypes. Overall, observed greatest divergence between PD, while exhibited an intermediate signature. DISCUSSION These results help explain clinicopathological this group provide unique insights into molecular mechanisms underlying pathogenesis NDDs.

Language: Английский

Citations

0