TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy

Identification: Leyns, Cheryl


Description

TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy
 
Cheryl E.G. Leynsa,c,d,1, Jason D. Ulrich a,c,d,1, Mary B. Finna,c,d, Floy R. Stewarta,c,d, Lauren J. Koscala,c,d, Javier Remolina Serranoa,c,d, Grace O. Robinsona,c,d, Elise Andersona,c,d, Marco Colonnab, and David M. Holtzmana,c,d,2
aDepartment of Neurology, bDepartment of Pathology and Immunology, cHope Center for Neurological Disorders, dKnight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO  63110
1CEGL and JDU equally contributed to this paper
2For correspondence contact David M. Holtzman, email: holtzman@wustl.edu
      
Variants in the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) have been found to increase the risk for developing sporadic, late-onset Alzheimer's disease (AD). TREM2 is expressed on microglia in the brain and its association with AD adds to increasing evidence implicating an active role for the innate immune system in AD initiation and progression. AD pathology is characterized first by the appearance of amyloid beta (Aβ) plaques followed by neurofibrillary tau tangles. Thus far, several studies have investigated the effects of TREM2 on Aβ plaques. One consistent observation has been that TREM2 knockdown or loss of TREM2 function reduces the number of plaque-associated microglia, which corresponds to an increase in neuronal damage surrounding plaques. Therefore, TREM2 is currently thought to be protective in the response to amyloid pathology while variants leading to a loss of TREM2 function impair microglia signaling and are deleterious. However, the potential role of TREM2 in the setting of pure tau pathology had not yet been characterized. To investigate whether TREM2 affected tau pathology, the microglial response to tau pathology, or tau-mediated neurodegeneration, we crossed TREM2+/+ (T2+/+) and TREM2-/- (T2-/-) mice to the P301S (PS) tau transgenic line, which expresses a mutant form of human tau that is causative for a familial form of frontotemporal dementia. Strikingly, T2-/-PS mice exhibited significantly less neurodegeneration as quantified by ventricular enlargement and preserved cortical volume in the entorhinal and piriform regions compared to T2+/+PS mice. However, no TREM2-dependent differences were observed for phosphorylated tau staining or insoluble tau levels. Rather, T2-/-PS mice exhibited significantly reduced microgliosis in the hippocampus and entorhinal cortex compared to T2+/+PS mice. Furthermore, gene expression analyses and immunostaining showed that glial reactivity was significantly attenuated in T2-/-PS mice and there were lower levels of inflammatory cytokines. These findings suggest that impairing microglia TREM2 signaling lowers neuroinflammation and is protective against neurodegeneration in the context of pure tauopathy.
 
This study was supported by the National Institute of Aging AG053976 (CEGL), JPB Foundation (DMH), The Donor's Cure Foundation (JDU), and the Cure Alzheimer's Fund (DMH, MC).
 

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