Differential Effects of Partial and Complete Loss of TREM2 on Microglial Injury Response and Tauopathy
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Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy Faten A. Sayeda,b,c, Maria Telpoukhovskaiac, Lay Kodamaa,b,c, Yaqiao Lic, Yungui Zhouc, David Lec, Axel Hauducc, Connor Ludwigc, Fuying Gaod,e, Claire Clellandb,c, Lihong Zhanc, Yonatan A. Cooperf, Dimitrios Davalosc,1, Katerina Akassogloub,c, Giovanni Coppolad,e, and Li Gana,b,c,2 aNeuroscience Graduate Program, University of California, San Francisco, CA 94158; bDepartment of Neurology, University of California, San Francisco, CA 94158; cGladstone Institute of Neurological Disease, San Francisco, CA 94158; dDepartment of Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; eDepartmentof Neurology, University of California, Los Angeles, CA 90095; and fHuman Genetics and Genomics Graduate Program, University of California, Los Angeles, CA 90095 Edited by Don W. Cleveland, University of California, San Diego, La Jolla, CA, and approved August 23, 2018 (received for review July 6, 2018) Alzheimer’s disease (AD), the most common form of dementia, is These findings highlight the need to assess the effects of TREM2 characterized by the abnormal accumulation of amyloid plaques haploinsufficiency in AD models. and hyperphosphorylated tau aggregates, as well as microgliosis. We investigated how TREM2 haploinsufficiency, a model Hemizygous missense variants in Triggering Receptor Expressed relevant to AD cases carrying hemizygous risk variants, affects on Myeloid Cells 2 (TREM2) are associated with elevated risk for microglial function and tau pathology. By using in vivo two- developing late-onset AD. These variants are hypothesized to photon microscopy to visualize microglial motility, we found result in loss of function, mimicking TREM2 haploinsufficiency. that TREM2 haploinsufficiency resulted in an age-dependent However, the consequences of TREM2 haploinsufficiency on tau impairment in microglial injury response without affecting pathology and microglial function remain unknown. We report baseline motility. Interestingly, complete loss of TREM2 the effects of partial and complete loss of TREM2 on microglial resulted in a milder impairment in injury-induced motility function and tau-associated deficits. In vivo imaging revealed compared with TREM2 haploinsufficiency. We then investi- that microglia from aged TREM2-haploinsufficient mice show a gated the effects of TREM2 haploinsufficiency and complete greater impairment in their injury response compared with micro- deficiency on tau pathology in mice expressing mutant human NEUROSCIENCE glia from aged TREM2-KO mice. In transgenic mice expressing tau (P301S). Our findings demonstrated a robust increase in mutant human tau, TREM2 haploinsufficiency, but not complete tau pathology in TREM2-haploinsufficient mice, an effect that loss of TREM2, increased tau pathology. In addition, whereas was not observed in TREM2-KO mice. We further investi- complete TREM2 deficiency protected against tau-mediated gated how TREM2 haploinsufficiency and complete defi- microglial activation and atrophy, TREM2 haploinsufficiency ele- ciency affect tau-mediated deficits. vated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathol- Significance ogy provide important insights into the critical role of TREM2 in AD pathogenesis. Late-onset Alzheimer’s disease is the most common form of dementia. A rare hemizygous variant in a microglial-expressed inflammation | motility | neurodegeneration | tau inclusions | RNA-seq gene, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), significantly increases risk for late-onset Alzheimer’s lzheimer’s disease (AD), the most common form of de- disease. This variant is thought to cause loss of function, in- Amentia, is characterized pathologically by the abnormal ducing TREM2 haploinsufficiency. The ramifications of TREM2 accumulation of amyloid plaques, hyperphosphorylated tau ag- haploinsufficiency on microglial function and tau pathology gregates, and microgliosis. The recent genetic implication of a are major gaps in the field. We find that, in contrast to the microglial-expressed gene, Triggering Receptor Expressed on protective effects of complete TREM2 deficiency, TREM2 hap- Myeloid Cells 2 (TREM2), in late-onset AD suggests a pivotal loinsufficiency exacerbates tau pathology, inflammation, and role for microglia in AD pathogenesis. Although mutations in atrophy at a late stage of disease in a mouse model of tau- opathy. The differential effects of partial and complete loss of TREM2 are rare, this gene is nonetheless the strongest immune TREM2 are important considerations for TREM2-targeted ther- gene-specific risk factor for AD discovered thus far (1–3). apeutic strategies. TREM2 encodes a transmembrane receptor that is expressed by microglia in the brain (4, 5). TREM2 has been implicated in Author contributions: F.A.S. and L.G. designed research; F.A.S., Y.Z., D.L., A.H., and D.D. neuroinflammation and in the metabolic fitness, proliferation, performed research; M.T., C.L., L.Z., Y.A.C., K.A., and G.C. contributed new reagents/ survival, and phagocytic capacity of microglia (6–16). analytic tools; F.A.S., M.T., L.K., Y.L., A.H., F.G., and L.G. analyzed data; and F.A.S., C.C., The most common AD-associated TREM2 variant, R47H, is and L.G. wrote the paper. associated with an approximately threefold increased risk for The authors declare no conflict of interest. developing late-onset AD (1–3). It is thought to result in a This article is a PNAS Direct Submission. TREM2 loss-of-function phenotype (10, 17, 18). Compared This open access article is distributed under Creative Commons Attribution-NonCommercial- with noncarriers, R47H carriers have higher levels of phos- NoDerivatives License 4.0 (CC BY-NC-ND). phorylated tau around plaques (19) and more neurofibrillary Data deposition: The data reported in this paper have been deposited in the Gene Ex- tangles (20). In addition, R47H carriers have higher levels of pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. cerebrospinal fluid (CSF)-soluble TREM2, and CSF-soluble GSE118630). TREM2 levels were significantly correlated with higher levels 1Present address: Department of Neurosciences, Lerner Research Institute, Cleveland of CSF-phosphorylated tau (21). These observations in hu- Clinic, Cleveland, OH 44195. man patients suggest a detrimental effect of TREM2 hap- 2To whom correspondence should be addressed. Email: [email protected]. loinsufficiency on tau pathology. Surprisingly, in a tauopathy This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. mouse model, complete loss of TREM2 function had no effect 1073/pnas.1811411115/-/DCSupplemental. on tau pathology, while protecting against brain atrophy (22). www.pnas.org/cgi/doi/10.1073/pnas.1811411115 PNAS Latest Articles | 1of6 Downloaded by guest on October 2, 2021 Results Baseline Baseline Ablation AB15 C 6 0.03 2 TREM2 Haploinsufficiency Causes an Age-Dependent Impairment in ’ 0.02 10 4 Microglia s Injury Response. Microglia carry out critical functions µm/sec) of surveying the brain and responding to injury (23, 24). To address the effect of TREM2 on microglial surveillance, we used 0.01 5 2 Total Change in Total Length (µm) – Speed per Average Process ( Number of Microglia in vivo two-photon imaging to examine microglial motility in 3 0.00 0 per 10,000 µm 0 + + + − − − 5-mo-old TREM2 / , TREM2 / and TREM2 / mice crossed to TREM2 +/+ –/–+/– TREM2 +/+ +/– –/– TREM2 +/+ +/– –/– GFP/+ Cx3cr1 D 3 min 21 min 39 min 57 min E mice, in which microglia express enhanced GFP 0.6 driven by the Cx3cr1 promoter (25). Analysis of a 10-min time- TREM2+/+ TREM2+/– lapse recording of cortical microglia showed no differences in the 0.4 TREM2–/– baseline properties of microglia across the three genotypes, in- WT cluding average speed of process extension and retraction and 0.2 A B HET total change in process length (Fig. 1 and ). TREM2 also had Response (a.u.) 0.0 no effect on microglial cell density or cell body size at baseline 20 40 60 (SI Appendix, Fig. S1 A and B). Moreover, in response to a laser- KO Time (min) TREM2+/+ induced focal tissue injury, microglia from young , FGBaseline 15 Baseline H 6 Ablation + − − − 2 TREM2 / and TREM2 / mice exhibited no difference in cell 0.03 10 4 density (Fig. 1C), cell body size (SI Appendix, Fig. S1C), or the 0.02 density of microglial processes extending toward the injury site 5 2 (Fig. 1 D and E and Movie S1). 0.01 Total Change in Length (µm) per 10,000 µm 0.00 0 Number of Microglia 0 Average Speed Per Given the established association of TREM2 with age-related Process (µm/sec) diseases (1–3, 26), we next examined the effects of TREM2 on TREM2 +/+ –/–+/– TREM2 +/+ +/– –/– TREM2 +/+ –/–+/– +/+ +/− microglial motility in 9–14-mo-old TREM2 , TREM2 and I 3 min 21 min 39 min 57 min J − − 0.5 TREM2+/+ TREM2 / mice. At baseline, the average speed and total change TREM2+/– 0.4 TREM2–/– **** F G **** in process length did not differ across genotypes (Fig. 1 and ). WT Microglial cell density or cell body size also remained similar (SI 0.3 **** Appendix,Fig.S1D and E). Strikingly, in response to focal tissue 0.2 + − TREM2 / HET 0.1 injury, microglia from older mice exhibited a signifi- Response (a.u.) cantly reduced response to injury compared