Description
TREM2 Supports the Beneficial Activation of Microglia and Promotes Survival in the SOD1G93A Mouse Model of ALS
Erica D Koval, Megan DenBleyker, Huo Li, Norm Allaire, Christopher J Roberts, and Karel Otero
Biogen, Cambridge, MA USA
ALS is a neurodegenerative disorder characterized by the selective loss of motor neurons in the brain and spinal cord. Microgliosis is a pathological hallmark in ALS patients and in the SOD1G93A rodent model. However, microglia function in ALS is poorly understood, and microglial anti-inflammatory strategies have failed in clinic to date.
TREM2 is an Ig-superfamily receptor expressed in microglia, and rare TREM2 variants have been implicated with an increased risk of developing various neurodegenerative disorders including Alzheimer's disease, Frontotemporal dementia, and possibly also ALS. Several postulated roles of TREM2 have been put forth including modulating phagocytosis, mediating cytokine release, supporting survival/proliferation, and more; however, the relevant mechanism of action of TREM2 in vivo remains unknown.
In SOD1G93A mice, we have characterized a robust upregulation in both the expression of TREM2 by microglia and in the number of TREM2+ microglia. Using fate-mapped mice that express GFP in microglia but not in blood monocytes, we found that >98% of the myeloid cells in end-stage SOD1G93A mouse spinal cord are GFP+ suggesting these proliferating myeloid cells to be endogenous microglia in origin.
SOD1G93A isolated microglia express a neurodegenerative specific transcriptional profile; however, TREM2 deficient microglia, measured at multiple disease stages, consistently experience a blunted adoption of this phenotype. In fact, 98% of the genes significantly modulated by both SOD1G93A and TREM2 genotype were positively correlated. Confirmed by histology, TREM2 deficient SOD1G93A microglia maintain expression of homeostatic markers and fail to robustly express activation markers, even during end-stage disease.
SOD1G93A TREM2 deficient mice did not have an altered onset of paresis symptoms as measured by rotarod, grip strength, and weight loss. However, post-onset, TREM2 deficient mice experienced an accelerated disease course resulting in a moderate but highly significant reduction in lifespan. We therefore put forward, contrary to previous dogma, that microglia activation is a TREM2-mediated protective mechanism. Therefore, we propose TREM2 agonism as a novel ALS therapeutic strategy warranting further research.