Distinct amyloid-β and tau-associated microglia profiles in Alzheimer’s disease
Top Cited Papers
Open Access
- 20 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Neuropathologica
- Vol. 141 (5), 681-696
- https://doi.org/10.1007/s00401-021-02263-w
Abstract
Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-β and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-β and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-β plaques or both amyloid-β plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-β load and localized to amyloid-β plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.Keywords
This publication has 42 references indexed in Scilit:
- Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2Genome Biology, 2014
- HTSeq—a Python framework to work with high-throughput sequencing dataBioinformatics, 2014
- Production of Tissue Microarrays, Immunohistochemistry Staining and Digitalization Within the Human Protein AtlasJournal of Visualized Experiments, 2012
- Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the LiteratureJournal of Neuropathology and Experimental Neurology, 2012
- National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approachActa Neuropathologica, 2011
- edgeR: a Bioconductor package for differential expression analysis of digital gene expression dataBioinformatics, 2009
- Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistryActa Neuropathologica, 2006
- Neuropathology of Alzheimer’s disease: a critical updateJournal of neural transmission. Supplementum, 1998
- Selective Expression of the Glutamate Receptor Channel δ2 Subunit in Cerebellar Purkinje CellsBiochemical and Biophysical Research Communications, 1993
- Neuropathological stageing of Alzheimer-related changesActa Neuropathologica, 1991