@article{bf938b1fdb3d4d21a474abb2e491aeb7,
title = "TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease",
abstract = "The microglial receptors CD33 and TREM2 have been associated with risk for Alzheimer's disease (AD). Here, we investigated crosstalk between CD33 and TREM2. We showed that knockout of CD33 attenuated amyloid beta (Aβ) pathology and improved cognition in 5xFAD mice, both of which were abrogated by additional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Aβ pathology and neurodegeneration but reduced Iba1+ cell numbers, all of which could not be rescued by additional CD33 knockout. RNA-seq profiling of microglia revealed that genes related to phagocytosis and signaling (IL-6, IL-8, acute phase response) are upregulated in 5xFAD;CD33−/− and downregulated in 5xFAD;TREM2−/− mice. Differential gene expression in 5xFAD;CD33−/− microglia depended on the presence of TREM2, suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2 includes regulation of the IL-1β/IL-1RN axis and a gene set in the “receptor activity chemokine” cluster. Our results should facilitate AD therapeutics targeting these receptors. Microglial receptors CD33 and TREM2 exhibit opposite effects on Aβ pathology and microglial activity in AD mice. In crosstalk between these receptors, TREM2 is required for differential gene expression in 5xFAD mice deficient for CD33 and acts downstream of CD33.",
keywords = "Alzheimer's, CD33, IL-1beta, RNA-seq, TREM2, amyloid beta, microglia, neuroinflammation, pathway analysis, transcriptomics",
author = "Ana Griciuc and Shaun Patel and Federico, {Anthony N.} and Choi, {Se Hoon} and Innes, {Brendan J.} and Oram, {Mary K.} and Gea Cereghetti and Danielle McGinty and Anthony Anselmo and Sadreyev, {Ruslan I.} and Hickman, {Suzanne E.} and {El Khoury}, Joseph and Marco Colonna and Tanzi, {Rudolph E.}",
note = "Funding Information: The research was supported by grants from the NIA/NIH ( K99AG049056 and 5R00AG049056 to A.G., 5R01MH060009 to R.E.T.), Cure Alzheimer's Fund (A.G. and R.E.T.), and JPB Foundation (R.E.T.). J.E.K. is supported by RF1 AG051506 . We thank the MGH Next Generation Sequencing Core, Adalis Maisonet, and Ulandt Kim for assistance in RNA-seq and DF/HCC Pathology Core for assistance in histopathology. Funding Information: The research was supported by grants from the NIA/NIH (K99AG049056 and 5R00AG049056 to A.G. 5R01MH060009 to R.E.T.), Cure Alzheimer's Fund (A.G. and R.E.T.), and JPB Foundation (R.E.T.). J.E.K. is supported by RF1 AG051506. We thank the MGH Next Generation Sequencing Core, Adalis Maisonet, and Ulandt Kim for assistance in RNA-seq and DF/HCC Pathology Core for assistance in histopathology. Conceptualization, A.G. and R.E.T.; Methodology, A.G. S.P. S.E.H. J.E.K. M.C. and R.E.T.; Software, S.P. A.N.F. A.A. and R.I.S.; Formal Analysis and Data Curation, A.G. S.P. A.N.F. and A.A.; Investigation, A.G. A.N.F. S.H.C. B.J.I. M.K.O. G.C. and D.M.; Resources, R.I.S. and M.C.; Writing ? Original, A.G. and R.E.T.; Writing ? Review and Editing, A.G. S.P. S.H.C. R.I.S. S.E.H. J.E.K. M.C. and R.E.T.; Visualization, A.G. S.P. A.N.F. S.H.C. and R.E.T.; Supervision, R.E.T.; Funding Acquisition, A.G. and R.E.T. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = sep,
day = "4",
doi = "10.1016/j.neuron.2019.06.010",
language = "English",
volume = "103",
pages = "820--835.e7",
journal = "Neuron",
issn = "0896-6273",
number = "5",
}