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Spatial Transcriptomics characterization of Alzheimer’s disease in the adult mouse brain
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.ORCID iD: 0000-0002-4035-5258
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is a devastating neurological disease associated with progressive loss of mental skills, cognitive and physical functions. Here, our goal was to uncover novel and known molecular targets in the structured layers of the hippocampus and olfactory bulbs that may contribute to hippocampal synaptic dysfunction and smelling defects in AD mice. Spatial Transcriptomics was used to identify high confidence genes that were differentially regulated in AD mice relative to controls. A discussion of how these genes may contribute to AD pathology is provided.

Keywords [en]
Alzheimer's disease, Spatial Transcriptomics, single cell RNA-seq
National Category
Medical and Health Sciences
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-262873OAI: oai:DiVA.org:kth-262873DiVA, id: diva2:1362987
Note

QC 20191023

Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2019-10-23Bibliographically approved
In thesis
1. Computational methods for analysis and visualization of spatially resolved transcriptomes
Open this publication in new window or tab >>Computational methods for analysis and visualization of spatially resolved transcriptomes
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Characterizing the expression level of genes (transcriptome) in cells and tis- sues is essential for understanding the biological processes of multicellular or- ganisms. RNA sequencing (RNA-seq) has gained traction in the last decade as a powerful tool that provides an accurate quantitative representation of the transcriptome in tissues. RNA-seq methods are, however, limited by the fact that they provide an average representation of the transcriptome across the tissue. Single cell RNA sequencing (scRNA-seq) provides quantitative gene expression levels of individual cells. This enables the molecular characteri- zation of cell types in health, disease and developmental tissues. However, scRNA-seq lacks the spatial context needed to understand how cells interact and their microenvironment. Current methods that provide spatially resolved gene expression levels are limited by a low throughput and the fact that the target genes must be known in advance.

Spatial Transcriptomics (ST) is a novel method that combines high-resolution imaging with high-throughput sequencing. ST provides spatially resolved gene expression levels in tissue sections. The first part of the work presented in this thesis (Papers I, II, III and IV) revolves around the ST method and the development of the computational tools required to process, analyse and visualize ST data.

Furthermore, the ST method was utilized to construct a three-dimensional (3D) molecular atlas of the adult mouse brain using 75 consecutive coronal sections (Paper V). We show that the molecular clusters obtained by unsu- pervised clustering of the atlas highly correlates with the Allen Brain Atlas. The molecular clusters provide new insights in the organization of regions like the hippocampus or the amygdala. We show that the molecular atlas can be used to spatially map single cells (scRNA-seq) onto the clusters and that only a handful of genes is required to define the brain regions at a molecular level.

Finally, the hippocampus and the olfactory bulb of transgenic mice mim- icking the Alzheimer’s disease (AD) were spatially characterized using the ST method (Paper VI). Dierential expression analysis revealed genes central in areas highly cited as important in AD including lipid metabolism, cellular bioenergetics, mitochondrial function, stress response and neurotransmission.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2019. p. 67
Series
TRITA-CBH-FOU ; 2019:54
Keywords
RNA, RNA-seq, single cell, scRNA-seq, transcriptomics, spatial transcriptomics, brain, 3D, Alzheimer’s disease
National Category
Medical and Health Sciences
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-262828 (URN)978-91-7873-335-4 (ISBN)
Public defence
2019-11-15, Air and Fire, Tomtebodavägen 23a, Solna, 10:00 (English)
Opponent
Supervisors
Note

QC 2019-10-23

Available from: 2019-10-23 Created: 2019-10-21 Last updated: 2019-10-23Bibliographically approved

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