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Prior Activation State Shapes the Microglia Response to Antihuman TREM2 in a Mouse Model of Alzheimer’S Disease

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Prior Activation State Shapes the Microglia Response to Antihuman TREM2 in a Mouse Model of Alzheimer’S Disease Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease Daniel C. Ellwangera,1, Shoutang Wangb,1, Simone Brioschib, Zhifei Shaoc, Lydia Greend, Ryan Casee, Daniel Yoof, Dawn Weishuhnd, Palaniswami Rathanaswamid, Jodi Bradleyg, Sara Raoc, Diana Chag, Peng Luanh, Shilpa Sambashivana, Susan Gilfillanb, Samuel A. Hassong, Ian N. Foltzd, Menno van Lookeren Campagnec,2, and Marco Colonnab,2 aGenome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080; bDepartment of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110; cDepartment of Inflammation and Oncology, Amgen Research, Amgen Inc., South San Francisco, CA 94080; dDepartment of Biologics Discovery, Amgen Research, Amgen Inc., Burnaby, BC, V5A1V7 Canada; eDiscovery Attribute Sciences, Amgen Research, Amgen Inc., South San Francisco, CA 94080; fDepartment of Biologics Optimization, Amgen Research, Amgen Inc., Thousand Oaks, CA 91320; gDepartment of Neuroscience, Amgen Research, Amgen Inc., Cambridge, MA 02142; and hDepartment of Translational Safety and Bioanalytical Sciences, Amgen Research, Amgen Inc., Thousand Oaks, CA 91320. Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved November 30, 2020 (received for review August 20, 2020) Triggering receptor expressed on myeloid cells 2 (TREM2) sustains accumulation also elicits a response by microglia, brain resident microglia response to brain injury stimuli including apoptotic cells, macrophages that support the development, function, and im- myelin damage, and amyloid β (Aβ). Alzheimer’s disease (AD) risk mune defense of the CNS (3). is associated with the TREM2R47H variant, which impairs ligand While all dominant mutations causing familial early-onset AD binding and consequently microglia responses to Aβ pathology. occur either in the substrate (amyloid precursor protein, APP) or Here, we show that TREM2 engagement by the mAb hT2AB as the proteases (presenilins) of the proteolytic pathway that gener- surrogate ligand activates microglia in 5XFAD transgenic mice that ates Aβ (4), genome-wide association studies found many genetic β accumulate A and express either the common TREM2 variant polymorphisms linked with late-onset AD in genes expressed by TREM2CV TREM2R47H TREM2CV IMMUNOLOGY AND INFLAMMATION ( )or . scRNA-seq of microglia from - microglia, such as triggering receptor expressed on myeloid 5XFAD mice treated once with control hIgG1 exposed four distinct cells 2 (TREM2), CD33, SPI1, SHIP1, and PLCγ2 (5, 6), pro- trajectories of microglia activation leading to disease-associated viding strong evidence that microglia actively control the onset (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II and/or progression of AD pathology (7). Microglia accumulate expressing (MHC-II) microglia types. All of these were underrepre- R47H around Aβ plaques to contain and compact them, thereby sented in TREM2 -5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. More- over, Cyc-M and IFN-R microglia were more abundant in female Significance than male TREM2CV-5XFAD mice, likely due to greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replen- Alzheimer’s disease (AD) is the most common dementia; no ished Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In therapy halts its progression. AD pathology, including amyloid- TREM2CV-5XFAD mice, however, hT2AB brought the representa- β (Aβ) plaques, neurofibrillary tangles, and synapse loss, trig- tion of male Cyc-M and IFN-R microglia closer to that of females, gers microglial responses that modulate disease course. The in which these trajectories had already reached maximum capac- TREM2 receptor promotes microglia responses to pathology ity. Moreover, hT2AB induced shifts in gene expression patterns in and a variant, TREM2R47H, impairs ligand binding and increases all microglial pools without affecting representation. Repeated AD risk. Employing scRNA-seq, we asked: can an anti-TREM2 treatment with a murinized hT2AB version over 10 d increased antibody, acting as a surrogate ligand, stimulate microglia in chemokines brain content in TREM2R47H-5XFAD mice, consistent mice that accumulate Aβ and express either the common with microglia expansion. Thus, the impact of hT2AB on microglia TREM2 variant (TREM2CV)orTREM2R47H? One systemic injec- is shaped by the extent of TREM2 endogenous ligand engagement tion of anti-TREM2 restored microglia activation in TREM2R47H and basal microglia activation. mice but promoted limited activation in mice carrying TREM2CV, which binds endogenous ligands. Thus, anti-TREM2 Alzheimer’s disease | microglia | TREM2 | amyloid beta | monoclonal can strengthen microglial responses during AD, contingent on antibody preexisting TREM2 engagement and basal activation. ’ Author contributions: S.W., I.N.F., M.v.L.C., and M.C. designed research; S.W., S.B., Z.S., lzheimer s disease (AD) is the most common cause of L.G., R.C., D.Y., D.W., P.R., J.B., S.R., D.C., P.L., S.S., S.G., and S.A.H. performed research; Aprogressive dementia in older adults; it affects more than D.C.E. and S.W. analyzed data; and D.C.E., S.W., M.v.L.C., and M.C. wrote the paper. 5.5 million Americans, most 65 y of age or older, and represents Competing interest statement: D.C.E., Z.S., L.G., R.C., D.Y., D.W., P.R., J.B., S.R., D.C., P.L., the sixth leading cause of death in the United States (https:// S.S., S.A.H., I.N.F., and M.v.L.C. are current employees or were past Amgen employees at www.nia.nih.gov/health/alzheimers-disease-fact-sheet). The path- the time when the experiments were performed. S.S. is Vice President of Nura Bio Inc. M.C. received research support from Amgen and serves on the Scientific Advisory Board ological features of AD include extracellular amyloid plaques of Vigil Neuroscience Inc. β β composed of the amyloid (A ) peptide, intraneuronal neuro- This article is a PNAS Direct Submission. fibrillary tangles consisting of aggregated, hyperphosphorylated Published under the PNAS license. tau protein, neuroimmune activation, and reductions in synaptic 1D.C.E. and S.W. contributed equally to this work. density (1). Longitudinal natural history studies, such as the 2To whom correspondence may be addressed. Email: [email protected] or Alzheimer’s Disease Neuroimaging Initiative, have demonstrated [email protected]. β that deposition of A in the central nervous system (CNS) occurs This article contains supporting information online at https://www.pnas.org/lookup/suppl/ early in disease and is followed by tau pathology, consequently doi:10.1073/pnas.2017742118/-/DCSupplemental. leading to neuronal cell death and cognitive impairment (2). Aβ Published January 14, 2021. PNAS 2021 Vol. 118 No. 3 e2017742118 https://doi.org/10.1073/pnas.2017742118 | 1of12 Downloaded by guest on September 28, 2021 reducing markers of axonal dystrophy in surrounding neurons (8). types in TREM2CV-5XFAD mice compared to TREM2R47H- − − During this process, microglia modify their phenotypic and tran- 5XFAD and Trem2 / -5XFAD mice. Further, Cyc-M and IFN-R scriptional properties, transitioning from a “homeostatic” to an microglia were more abundant in females than males, which activated profile often defined as disease-associated microglia correlated with a higher degree of Aβ accumulation in females. (DAM) (6). This transition to the DAM phenotype is robustly hT2AB promoted cell cycle re-entry in TREM2R47H-5XFAD mice activated in transgenic amyloid murine models of AD (9, 10) but is and promoted Cyc-M expansion more effectively in males than in observed to a lesser extent in some human AD postmortem brains females within the TREM2CV-5XFAD cohort. Likewise, hT2AB (11, 12), potentially reflecting insufficient microglial response to induced the terminal IFN-R population in TREM2R47H-5XFAD CNS damage in individuals who develop AD pathology. of both sexes, as well as TREM2CV-5XFAD males, but did not Microglia transition to DAM has been shown to depend on promote this cell fate in TREM2CV-5XFAD females, in which this TREM2, a macrophage cell surface receptor abundantly expressed population was already robustly induced. Thus, mAb-mediated in microglia (13). TREM2 is a member of the immunoglobulin engagement of TREM2 mainly increased Cyc-M and IFN-R superfamily that binds phospholipids, apoptotic cells, lipoproteins fates in microglia where TREM2 engagement is deficient or (such as high-density lipoprotein, low-density lipoprotein, and suboptimal. Analysis of expression dynamics of individual genes ApoE), and Aβ. TREM2 transmits intracellular signals through the showed that hT2AB costimulated expression changes as soon as associated adaptor DAP12, which recruits the protein tyrosine ki- cell fates were determined but did not alter the transcriptional nase Syk, leading to a cascade of protein tyrosine phosphorylation identity of the terminal cell types. events that promote proliferation, survival, production of adenosine We finally tested the effect of mT2AB on brain biochemical triphosphate, and protein biosynthesis. The ectodomain of TREM2 analytes and histological images in the 5XFAD mice after re- is cleaved from the cell surface by proteases, thereby limiting peated injections every 3 d for a short period of time. mT2AB TREM2 signaling and releasing soluble TREM2 (sTREM2) (14, treatment resulted in the greatest increases in CCL4, CXCL10, 15). Genetic variants in TREM2 are
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