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Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease
- Publication Year :
- 2020
-
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.
- Subjects :
- 0301 basic medicine
Male
Transcription, Genetic
Inbred C57BL
Transgenic
Transcriptome
Mice
0302 clinical medicine
Immunologic
Receptors
Receptors, Immunologic
Receptor
education.field_of_study
Membrane Glycoproteins
Microglia
Brain
General Medicine
Middle Aged
Phenotype
Cell biology
Oligodendroglia
medicine.anatomical_structure
030220 oncology & carcinogenesis
Female
Transcription
Astrocyte
Population
Mice, Transgenic
Biology
Aged
Alzheimer Disease
Amyloid beta-Peptides
Animals
Astrocytes
Axons
Cell Nucleus
Humans
Mice, Inbred C57BL
Nerve Degeneration
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Genetic
medicine
education
TREM2
Oligodendrocyte
030104 developmental biology
nervous system
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....1f710a0b2b775974327693925d2167f3