Abstract
Microglia are the tissue-resident macrophages of the central nervous system (CNS). Recent studies based on bulk and single-cell RNA sequencing in mice indicate high relevance of microglia with respect to risk genes and neuro-inflammation in Alzheimer’s disease (AD). Here, we investigated microglia transcriptomes at bulk and single-cell levels in non-demented elderly and AD donors using acute human postmortem cortical brain samples. We identified seven human microglial subpopulations with heterogeneity in gene expression. Notably, gene expression profiles and subcluster composition of microglia did not differ between AD donors and non-demented elderly in bulk RNA sequencing nor in single-cell sequencing.
Highlights
Alzheimer’s disease (AD), one of the most prevalent age-related neurodegenerative disorders, is characterized by extracellular deposition of β-amyloid protein (Aβ) and intraneuronal neurofibrillary tangles in the neocortex (Hyman and Trojanowski, 1997).Functional changes occurring in microglia cells have been proposed as an important factor in AD pathology (Zhang et al, 2013; Mhatre et al, 2015)
We aimed to identify transcriptomic changes in human microglia at the end stage of AD by applying both bulk and scRNAseq of microglia acutely isolated from postmortem central nervous system (CNS) tissue
The samples were classified into three experimental groups based on a clinical diagnostic report provided by the Netherlands Brain Bank/NeuroBiobank Born-Bunge and immunohistochemical analysis of Aβ and hyperphosphorylated tau (PHF-tau): CTR, CTR with plaques (CTR+, no dementia, presence of Aβ plaques and/or PHF-tau, n = 9), and AD
Summary
Functional changes occurring in microglia cells have been proposed as an important factor in AD pathology (Zhang et al, 2013; Mhatre et al, 2015). AD single nucleotide polymorphism heritability was recently found to be highly enriched in microglia enhancers (Nott et al, 2019). Multiple genes associated with increased susceptibility for sporadic AD are preferentially expressed in microglia, including APOE, CR1, CD33, INPP5D, PLCG2, MS4A6A, and TREM2 (Ulrich et al, 2014; Sarlus and Heneka, 2017). The functional changes occurring in microglia during AD pathology seem to be diverse (Friedman et al, 2018), and the exact role that microglia play in AD pathology is still unknown
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