Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease
Top Cited Papers
- 1 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 26 (1), 131-142
- https://doi.org/10.1038/s41591-019-0695-9
Abstract
Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1 AG051485, R21 AG059176, RF1 AG059082, RF1 AG047644)
- Cure Alzheimer’s Fund
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01 NS090934)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R15 GM119070)
This publication has 64 references indexed in Scilit:
- Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid BetaNeuron, 2013
- Epidermal growth factor receptor is a preferred target for treating Amyloid-β–induced memory lossProceedings of the National Academy of Sciences of the United States of America, 2012
- Increasing the Multiplexing Capacity of TMTs Using Reporter Ion Isotopologues with Isobaric MassesAnalytical Chemistry, 2012
- A Tissue-Specific Atlas of Mouse Protein Phosphorylation and ExpressionCell, 2010
- YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer's DiseaseBiological Psychiatry, 2010
- Target-Decoy Search Strategy for Mass Spectrometry-Based ProteomicsPublished by Springer Science and Business Media LLC ,2009
- Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque FormationJournal of Neuroscience, 2006
- A probability-based approach for high-throughput protein phosphorylation analysis and site localizationNature Biotechnology, 2006
- A4POE*4-associated Alzheimer's disease risk is modified by α1–antichymotrypsin polymorphismNature Genetics, 1995
- Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filamentsNature, 1994