Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease

By Yingyue Zhou, Wilbur M Song, P. Andhey, A. Swain, T. Levy, K. Miller, P. L. Poliani, Manuela Cominelli, Shikha Grover, S. Gilfillan and 15 more. Nature Medicine, 2020

748 citations recorded by the source corpus.

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. Single-nucleus RNA sequencing in a mouse model of Aβ accumulation and postmortem brain tissue from people with Alzheimer’s disease reveals substantial species-specific differences in transcriptional signatures, but both point to the contribution of glia and the importance of TREM2.

Subfields: Complementary and alternative medicine, Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/99ea49ab0c1c1672b94039e5c61e1144b048cb80

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Citations in the corpus

hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023, methodology): “(C) Violin plots showing distributions of EGAD(23) neighbor-voting area under the receiver operating characteristic curve (AUC) scores in each of the cell-typespecific co-expression networks from the human PFC dataset.(11) (D) Violin plots showing distributions of multifunctionality AUC scores in ea”
Microglia states and nomenclature: A field at its crossroads (2022, neutral): “58,59,85,121 How the TREM2 receptor drives the DAM transcriptional phenotype remains unclear, although the TREM2-ApoE signaling pathway is necessary for the switch from homeostatic to MGnD. 59 Further investigations are required to fully elucidate the role of TREM2.”