Single-cell transcriptomic analysis of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder, the molecular and cellular complexity of which remains poorly understood. Here, we profiled and analysed 80,660 single-nucleus transcriptomes from prefrontal cortex of 48 individuals with varying degrees of AD pathology. We identified transcriptionally-distinct subpopulations across six major brain cell-types, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest AD-associated changes appeared early in pathological progression and were highly cell-type-specific, whereas genes upregulated in late-stage were common across cell types and primarily involved in global stress response. Surprisingly, we found an overrepresentation of female cells in AD-associated subpopulations, and substantially different transcriptional responses between sexes in multiple cell types, including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting a key role in AD pathophysiology. Our single-cell transcriptomic resource provides a first blueprint for interrogating the molecular underpinnings and cellular basis of AD.

Transcriptional profiling of microglia; current state of the art and future perspectives

“…The number of microglia in the brain is relatively low (Keller, Ero, & Markram, ) and, as a consequence the number of microglia in total CNS tissue single cell sequencing data is also relatively low (Darmanis et al, ; Mathys et al, ). In order to enrich for microglia nuclei from frozen tissue, nuclei from neurons and oligodendrocytes were labeled with antibodies against NeuN and OLIG2 and selected against during FACS isolations.…”

“…SnRNAseq was used to elucidate the transcriptomic changes underlying AD (Mathys et al, ). Mathys et al isolated 80,660 nuclei from 48 individuals followed by droplet‐based single‐nucleus sequencing.…”

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…Another important cell category is the microglia-macrophage-like cells important for scavenging cellular debris and protein aggregates, but when activated they also become central players in brain inflammation. With the available data from the normal unperturbed situation as a benchmark, gene expression changes related to diseases now start to be elucidated, for example, in Alzheimer's disease (AD) [11] and multiple sclerosis [12], where single-nuclei RNA sequencing technology has been used to capture transcriptomes at single-cell resolution. Thus, more than 500 molecularly distinct classes of neurons and glial cells have been identified in the mouse brain [1,2], and information about the cellular composition of specific brain regions is increasing rapidly [2][3][4][5][6][7][8].…”

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

“…Murine scRNA‐seq studies have advanced the characterization of OL‐lineage transcriptomic signatures, with several studies identifying intermediate states between progenitors and fully differentiated cells (Artegiani et al, ; Marques et al, ; reviewed in van Bruggen, Agirre, & Castelo‐Branco, ). Human tissue‐based studies that focus on OL‐lineage cells have applied sequencing of nuclei (snRNA‐seq) derived from postmortem tissues from adult “control” donors and individuals with clinical conditions that include MS (Jakel et al, ; Schirmer et al, ), Alzheimer's disease (Mathys et al, ), and autism (Velmeshev et al, ). However, studies of human OL‐lineage development remain limited by the availability of whole cell samples that would permit inclusion of non‐nuclear RNAs, and material that encompasses a wide age span including time of peak myelination.…”