Guidelines for bioinformatics of single-cell sequencing data analysis in Alzheimer’s disease: review, recommendation, implementation and application

Wang, Minghui; Song, Won‐Min; Ming, Chi; Wang, Qian; Zhou, Xianxiao; Xu, Peng; Krek, Azra; Yoon, Yong-Joong; Ho, Lap; Orr, Miranda E.; Yuan, Guo‐Cheng; Zhang, Bin

doi:10.1186/s13024-022-00517-z

Cited by 50 publications

(44 citation statements)

References 562 publications

(901 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The expression profiles of each cell using the 2000 most variable genes as measured by dispersion ( 41 , 42 ) were used for neighborhood graph generation and dimensionality reduction with t-distributed stochastic neighbour embedding (tSNE) or UMAP ( 43 ). Clustering was performed on this neighborhood graph using the Leiden community detection algorithm ( 44 ).…”

Section: Methodsmentioning

confidence: 99%

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1

et al. 2022

View full text Add to dashboard Cite

BACE-1 is required for generating β-amyloid (Aβ) peptides in Alzheimer’s disease (AD). Here, we report that microglial BACE-1 regulates the transition of homeostatic to stage 1 disease-associated microglia (DAM-1) signature. BACE-1 deficiency elevated levels of transcription factors including Jun , Jund , Btg2 , Erg1 , Junb , Fos , and Fosb in the transition signature, which transition from more homeostatic to highly phagocytic DAM-1. Consistently, similar transition-state microglia in human AD brains correlated with lowered levels of BACE-1 expression. Targeted deletion of Bace-1 in adult 5xFAD mice microglia elevated these phagocytic microglia, correlated with significant reduction in amyloid plaques without synaptic toxicity. Silencing or pharmacologically inhibiting BACE-1 in cultured microglia-derived cells shows higher phagocytic function in microglia. Mechanistic exploration suggests that abolished cleavage of IL-1R2 and Toll-like receptors via BACE-1 inhibition contributes to the enhanced signaling via the PI3K and p38 MAPK kinase pathway. Together, targeted inhibition of BACE-1 in microglia may offer AD treatment.

show abstract

Section: Methodsmentioning

confidence: 99%

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Emerging sc/snRNA-seq approaches not only have become vital tools for dissecting heterogeneity and composition of cell types, but also provided significant insights into molecular mechanisms for complex human diseases such as Alzheimer's disease (see our review) 39 . Here we profiled 315,867 single nuclei, which is unprecedent, in the human SN from 32 postmortem brains including PD and controls of an average age at 81.…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomic atlas of the human substantia nigra in Parkinson’s disease

Wang

Choi

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Parkinson′s disease (PD) is a common and complex neurodegenerative disorder. Loss of neuromelanin–containing dopaminergic (DA) neurons in the substantia nigra (SN) is a hallmark of PD neuropathology, however, the etiology of PD remains unclear. Single–cell (–nucleus) RNA sequencing (sc or snRNAseq) has significantly advanced our understanding of neurodegenerative diseases including Alzheimer′s, but limited progress has been made in PD. Here we generated by far the largest snRNAseq data of high–quality 315,867 nuclei from the human SN including 9 healthy controls and 23 idiopathic PD cases across different Braak stages. Clustering analysis identified major brain cell types including DA neurons, excitatory neurons, inhibitory neurons, glial cells, endothelial, pericytes, fibroblast and T-cells in the human SN. By combining immunostaining and validating against the datasets from independent cohorts, we identified three molecularly distinct subtypes of DA–related neurons, including a RIT2–enriched population, in human aged SN. All DA neuron subtypes degenerated in PD, whereas the composition of non-neuronal cell clusters including major glial types showed little change. Our study delineated cell–type–specific PD–linked gene expression in the SN and their alterations in PD. Examination of cell–type–based transcriptomic changes suggests the complexity and diversity of molecular mechanisms of PD. Analysis of the remaining DA neurons of the three subtypes from PD demonstrated alterations of common gene sets associated with neuroprotection. Our findings highlight the heterogeneity of DA neurons in the human SN and suggest molecular basis for vulnerability and resilience of human DA neurons in PD. Our cohort thus provides a valuable resource for dissecting detailed mechanisms of DA neuron degeneration and identifying new neuroprotective strategies for PD.

show abstract

“…Nevertheless, studies on the proteomic changes in the plasma or serum of AD patients are still very rare, due to the technical limitations and complex proteomic changes in serum [ 28 ]. The advent of single-cell sequencing technology provides an effective method for studying the cellular heterogeneity in the brain and provides an approach to discover cell-specific biomarkers [ 29 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Cortex Single-Cell Transcriptome and Serum Proteome Reveals the Novel Biomarkers in Alzheimer’s Disease

Feng

Shi

et al. 2022

Brain Sciences

View full text Add to dashboard Cite

Blood-based proteomic analysis is a routine practice for detecting the biomarkers of human disease. The results obtained from blood alone cannot fully reflect the alterations of nerve cells, including neurons and glia cells, in Alzheimer’s disease (AD) brains. Therefore, the present study aimed to investigate novel potential AD biomarker candidates, through an integrated multi-omics approach in AD. We propose a comprehensive strategy to identify high-confidence candidate biomarkers by integrating multi-omics data from AD, including single-nuclei RNA sequencing (snRNA-seq) datasets of the prefrontal and entorhinal cortices, as wells as serum proteomic datasets. We first quantified a total of 124,658 nuclei, 8 cell types, and 3701 differentially expressed genes (DEGs) from snRNA-seq dataset of 30 human cortices, as well as 1291 differentially expressed proteins (DEPs) from serum proteomic dataset of 11 individuals. Then, ten DEGs/DEPs (NEBL, CHSY3, STMN2, MARCKS, VIM, FGD4, EPB41L2, PLEKHG1, PTPRZ1, and PPP1R14A) were identified by integration analysis of snRNA-seq and proteomics data. Finally, four novel candidate biomarkers (NEBL, EPB41L2, FGD4, and MARCKS) for AD further stood out, according to bioinformatics analysis, and they were verified by enzyme-linked immunosorbent assay (ELISA) verification. These candidate biomarkers are related to the regulation process of the actin cytoskeleton, which is involved in the regulation of synaptic loss in the AD brain tissue. Collectively, this study identified novel cell type-related biomarkers for AD by integrating multi-omics datasets from brains and serum. Our findings provided new targets for the clinical treatment and prognosis of AD.

show abstract

Guidelines for bioinformatics of single-cell sequencing data analysis in Alzheimer’s disease: review, recommendation, implementation and application

Cited by 50 publications

References 562 publications

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1

Single-cell transcriptomic atlas of the human substantia nigra in Parkinson’s disease

Integrated Analysis of Cortex Single-Cell Transcriptome and Serum Proteome Reveals the Novel Biomarkers in Alzheimer’s Disease

Contact Info

Product

Resources

About