Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease
Autor: | Marco Colonna, Konstantin Zaitsev, David M. Holtzman, Makoto Sainouchi, Manuela Cominelli, Akiyoshi Kakita, David A. Bennett, Susan Gilfillan, Marina Cella, Sean A. Beausoleil, Takeshi Ikeuchi, Tyler K. Ulland, Shikha Grover, Prabhakar S. Andhey, Kelly R. Miller, Michael R. Nichols, Tyler Levy, Julie A. Schneider, Wilbur M. Song, Amanda Swain, Jason D. Ulrich, Akinori Miyashita, Maxim N. Artyomov, Yingyue Zhou, Pietro Luigi Poliani |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
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 |
Popis: | 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. |
Databáze: | OpenAIRE |
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