Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer‚Äôs disease
Authors: Michael R Nichols
Akinori Miyashita
Akiyoshi Kakita
Amanda Swain
Makoto Sainouchi
Konstantin Zaitsev
Marina Cella
Julie A Schneider
Sean A Beausoleil
Kelly R Miller
Susan Gilfillan
David A Bennett
Wilbur M Song
Takeshi Ikeuchi
Maxim N Artyomov
Yingyue Zhou
Prabhakar S Andhey
Jason D Ulrich
Tyler Levy
Marco Colonna
Shikha Grover
David M Holtzman
Tyler K Ulland
Pietro L Poliani
Manuela Cominelli
Journal: Nature Medicine (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Glia; Alzheimer's disease; TREM2; microglia; DAM
Affiliations: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA., Bluefin Biomedicine, Beverly, MA, USA., NanoString, Seattle, WA, USA., Pathology Unit, Molecular and Translational Medicine Department, University of Brescia, Brescia, Italy., Department of Chemistry & Biochemistry, University of Missouri-St. Louis, St. Louis, MO, USA., Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA., Computer Technologies Department, ITMO University, Saint Petersburg, Russia., Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan., Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan., Rush Alzheimer's Disease Center and Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA., Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University School of Medicine, St. Louis, MO, USA., Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. .

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. 

Retracted: No

PubPeer comments:
 This report provides invaluable resources for the research community. One major concern is a lack of rigor in the design of their proteomics study. Given the sex difference in amyloid level between male and female 5x FAD mouse model, this study design is based on only N=1 per group. It appears that the authors inappropriately combined data from male N=1 and female N=1 into one group. In addition, it is unclear why proteomics data was not deposited to http: www.proteomexchange.org or any other public data repository whereas snRNA-seq data was deposited to the AD Knowledge Portal. Given the fact that this data was from animals, not humans, there should not be any confidentiality issue. TMT-Channel Sample 126 KO Male : KO Female=1:1 Mix 127 N R47H Male 127 C R47H Female 128 N CV Male 128 C CV Female 129 N 5XFAD KO Male 129 C 5XFAD KO Female 130 N 5XFAD R47H Male 130 C 5x FAD R47H Female 131 N 5x FAD CV Male 131 C 5x FAD CV Female I think the authors need to remove this underpowered N=1 per group proteomics data. If they insist to include this proteomics data, this data should be deposited to the public repository so that others can validate the statistics reported in this paper. I believe removing the underpowered proteomics data does not decrease the significance and validity of this important study. ,