Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.
Aged
Alzheimer Disease
/ genetics
Amyloid beta-Peptides
/ metabolism
Animals
Astrocytes
/ metabolism
Axons
/ pathology
Brain
/ metabolism
Cell Nucleus
/ metabolism
Female
Humans
Male
Membrane Glycoproteins
/ metabolism
Mice, Inbred C57BL
Mice, Transgenic
Microglia
/ metabolism
Middle Aged
Nerve Degeneration
/ pathology
Oligodendroglia
/ metabolism
Receptors, Immunologic
/ metabolism
Transcription, Genetic
Transcriptome
/ genetics
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
05
06
2019
accepted:
11
11
2019
entrez:
15
1
2020
pubmed:
15
1
2020
medline:
14
4
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31932797
doi: 10.1038/s41591-019-0695-9
pii: 10.1038/s41591-019-0695-9
pmc: PMC6980793
mid: NIHMS1542659
doi:
Substances chimiques
Amyloid beta-Peptides
0
Membrane Glycoproteins
0
Receptors, Immunologic
0
TREM2 protein, human
0
Trem2 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
131-142Subventions
Organisme : NINDS NIH HHS
ID : R01 NS090934
Pays : United States
Organisme : NIGMS NIH HHS
ID : R15 GM119070
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG017917
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG059176
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007200
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG010161
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG047644
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG059082
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG051485
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG015819
Pays : United States
Commentaires et corrections
Type : ErratumIn
Références
Long, J. M. & Holtzman, D. M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179, 312–339 (2019).
pubmed: 31564456
pmcid: 6778042
De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016).
Heneka, M. T., Golenbock, D. T. & Latz, E. Innate immunity in Alzheimer’s disease. Nat. Immunol. 16, 229–236 (2015).
pubmed: 25689443
Griciuc, A. et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643 (2013).
pubmed: 3706457
pmcid: 3706457
Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–369 (2015).
pubmed: 25693568
pmcid: 4530583
Seyfried, N. T. et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer’s disease. Cell Syst. 4, 60–72.e4 (2017).
pubmed: 27989508
Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).
pubmed: 28546318
pmcid: 5858585
Olah, M. et al. A transcriptomic atlas of aged human microglia. Nat. Commun. 9, 539 (2018).
pubmed: 29416036
pmcid: 5803269
Masuda, T. et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566, 388–392 (2019).
pubmed: 30760929
pmcid: 30760929
Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e17 (2017).
pubmed: 28602351
pmcid: 28602351
Krasemann, S. et al. The TREM2–APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581.e9 (2017).
pubmed: 28930663
pmcid: 28930663
Mathys, H. et al. temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366–380 (2017).
pubmed: 29020624
pmcid: 5642107
Bohlen, C. J., Friedman, B. A., Dejanovic, B. & Sheng, M. Microglia in brain development, homeostasis, and neurodegeneration. Annu. Rev. Genet. https://doi.org/10.1146/annurev-genet-112618-043515 (2019).
doi: 10.1146/annurev-genet-112618-043515
pubmed: 31518519
Ulland, T. K. & Colonna, M. TREM2 - a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol. 14, 667–675 (2018).
pubmed: 30266932
Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).
pubmed: 4477963
pmcid: 4477963
Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015).
pubmed: 25732305
pmcid: 4354365
Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745 (2018).
pubmed: 29321225
pmcid: 5839761
Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016).
pubmed: 27196974
pmcid: 4898967
Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).
pubmed: 27091843
pmcid: 4854736
Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019).
pubmed: 6865822
pmcid: 6865822
Jäkel, S. et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543–547 (2019).
pubmed: 30747918
pmcid: 6544546
Oakley, H. et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations:potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006).
pubmed: 17021169
pmcid: 6674618
Mucke, L. et al. Astroglial expression of human α
pubmed: 11106573
pmcid: 1885780
Nilsson, L. N. et al. α-1-antichymotrypsin promotes β-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer’s disease. J. Neurosci. 21, 1444–1451 (2001).
pubmed: 11222634
pmcid: 6762932
Winkler, C. & Yao, S. The midkine family of growth factors: diverse roles in nervous system formation and maintenance. Br. J. Pharmacol. 171, 905–912 (2014).
pubmed: 24125182
pmcid: 3925029
Molinuevo, J. L. et al. Current state of Alzheimer’s fluid biomarkers. Acta Neuropathol. (Berl.) 136, 821–853 (2018).
Masuda, T. et al. IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Rep. 1, 334–340 (2012).
pubmed: 22832225
pmcid: 4158926
Vardarajan, B. N. et al. Coding mutations in SORL1 and Alzheimer’s disease. Ann. Neurol. 77, 215–227 (2015).
pubmed: 25382023
pmcid: 4367199
Angelova, D. M. & Brown, D. R. Microglia and the aging brain: are senescent microglia the key to neurodegeneration? J. Neurochem. https://doi.org/10.1111/jnc.14860 (2019).
doi: 10.1111/jnc.14860
pubmed: 31478208
Ioannou, M. S. et al. Neuron–astrocyte metabolic coupling protects against activity-induced fatty acid toxicity. Cell 177, 1522–1535.e14 (2019).
pubmed: 31130380
McKeon, R. J., Jurynec, M. J. & Buck, C. R. The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. J. Neurosci. 19, 10778–10788 (1999).
pubmed: 10594061
pmcid: 6784959
Schultz, C. C. et al. Common variation in NCAN, a risk factor for bipolar disorder and schizophrenia, influences local cortical folding in schizophrenia. Psychol. Med. 44, 811–820 (2014).
pubmed: 23795679
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
pubmed: 5404890
pmcid: 5404890
Richter-Landsberg, C. The cytoskeleton in oligodendrocytes. Microtubule dynamics in health and disease. J. Mol. Neurosci. MN 35, 55–63 (2008).
pubmed: 18058074
Mecollari, V., Nieuwenhuis, B. & Verhaagen, J. A perspective on the role of class III semaphorin signaling in central nervous system trauma. Front. Cell. Neurosci. 8, 328 (2014).
pubmed: 25386118
pmcid: 4209881
Wang, H. et al. miR-219 Cooperates with miR-338 in myelination and promotes myelin repair in the CNS. Dev. Cell 40, 566–582.e5 (2017).
pubmed: 28350989
pmcid: 5569304
Wang, L. et al. Epidermal growth factor receptor is a preferred target for treating amyloid-β-induced memory loss. Proc. Natl Acad. Sci. USA 109, 16743–16748 (2012).
pubmed: 23019586
pmcid: 3478595
Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018).
pubmed: 6422159
pmcid: 6422159
Dickey, C. A. et al. Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J. Neurosci. 23, 5219–5226 (2003).
pubmed: 12832546
pmcid: 6741153
Han, P. et al. Association of pituitary adenylate cyclase-activating polypeptide with cognitive decline in mild cognitive impairment due to Alzheimer disease. JAMA Neurol. 72, 333–339 (2015).
pubmed: 25599520
pmcid: 5924703
Harboe, M., Torvund-Jensen, J., Kjaer-Sorensen, K. & Laursen, L. S. Ephrin-A1–EphA4 signaling negatively regulates myelination in the central nervous system. Glia 66, 934–950 (2018).
pubmed: 29350423
Tozaki-Saitoh, H. et al. Transcription factor MafB contributes to the activation of spinal microglia underlying neuropathic pain development. Glia 67, 729–740 (2019).
pubmed: 30485546
Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019).
pubmed: 30936558
pmcid: 6605052
Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).
pubmed: 27033548
pmcid: 5094372
Ma, J., Yee, A., Brewer, H. B., Das, S. & Potter, H. Amyloid-associated proteins α
pubmed: 7969426
Kamboh, M. I., Sanghera, D. K., Ferrell, R. E. & DeKosky, S. T. APOE*4-associated Alzheimer’s disease risk is modified by α1-antichymotrypsin polymorphism. Nat. Genet. 10, 486–488 (1995).
pubmed: 7670501
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).
pubmed: 6700744
pmcid: 6700744
Finak, G. et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015).
pubmed: 4676162
pmcid: 4676162
Geiss, G. K. et al. Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat. Biotechnol. 26, 317–325 (2008).
pubmed: 18278033
McAlister, G. C. et al. MultiNotch MS3 enables accurate, sensitive and multiplexed detection of differential expression across cancer cell line proteomes. Anal. Chem. 86, 7150–7158 (2014).
pubmed: 4215866
pmcid: 4215866
Huttlin, E. L. et al. A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143, 1174–1189 (2010).
pubmed: 21183079
pmcid: 3035969
Elias, J. E. & Gygi, S. P. Target-decoy search strategy for mass spectrometry-based proteomics. Methods Mol. Biol. Clifton NJ 604, 55–71 (2010).
McAlister, G. C. et al. Increasing the multiplexing capacity of TMTs using reporter ion isotopologues with isobaric masses. Anal. Chem. 84, 7469–7478 (2012).
pubmed: 22880955
pmcid: 3715028
Beausoleil, S. A., Villén, J., Gerber, S. A., Rush, J. & Gygi, S. P. A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat. Biotechnol. 24, 1285–1292 (2006).
Stine, W. B., Jungbauer, L., Yu, C. & LaDu, M. J. Preparing synthetic Aβ in different aggregation states. Methods Mol. Biol. Clifton NJ 670, 13–32 (2011).
Gouwens, L. K. et al. Aβ42 protofibrils interact with and are trafficked through microglial-derived microvesicles. ACS Chem. Neurosci. 9, 1416–1425 (2018).
pubmed: 29543435
Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).
pubmed: 6447622
pmcid: 6447622