TREM2 Haploinsufficiency Impairs Microglia's Response to Injury and Exacerbates Tau Pathology in a Tauopathy Mouse Model
Faten A. Sayed1,2,3, Maria Telpoukhovskaia1,Yaqiao Li1, Yungui Zhou1, David Le1, Axel Hauduc4, Connor Ludwig1, Fuying Gao5, Claire Clelland1,3, Lihong Zhan1, Dimitrios Davalos1, Katerina Akassoglou1,3, Giovanni Coppola5, Li Gan1,2,3 1Gladstone Institutes, San Francisco, CA; 2Neuroscience Graduate Program, University of California, San Francisco; 3Department of Neurology, University of California, San Francisco; 4University of California, Berkeley; 5Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles
Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with significantly increased risk for developing late-onset Alzheimer's disease. These variants are hypothesized to result in loss-of-function, mimicking TREM2 haploinsufficiency. Yet, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report that TREM2 haploinsufficiency, but not complete loss of TREM2, impairs microglial function and elevates tau pathology. In vivo imaging revealed that microglia from aged TREM2 haploinsufficient mice show an impaired injury response, while those from aged TREM2 knockout mice were not significantly impaired. RNA-sequencing and pathway analyses ranked cellular movement as one of the most significantly altered pathways in TREM2+/- microglia compared to those from TREM2+/+. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. TREM2 haploinsufficiency also elevated expression of pro-inflammatory markers without exacerbating tau-mediated neuronal loss. The detrimental effects of TREM2 haploinsufficiency on microglial function and tau pathology provide important insight into the critical role of TREM2 in AD pathogenesis.