Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice

Abstract

Tau pathology is a pathological hallmark for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia. As a novel susceptibility gene for these 2 diseases, triggering receptor expressed on myeloid cells 2 (TREM2) gene encodes an immune receptor that is uniquely expressed by microglia. Recently, a correlation between TREM2 expression and hyperphosphorylated tau has been revealed in the brain of Alzheimer's disease patients, suggesting a potential association between TREM2 and tau pathology. However, the role of TREM2 in tau pathology remains unclear thus far. Herein, using P301S mice, we showed that TREM2 was upregulated in microglia during disease progression. Silencing of brain TREM2 exacerbated tau pathology in P301S mice. This exacerbation might be attributed to neuroinflammation-induced hyperactivation of tau kinases. Additionally, more severe neurodegenerative changes and spatial learning deficits were observed following TREM2 silencing. Our results imply that TREM2 attenuates tau kinase activity through restriction of neuroinflammation, and thus protects against tau pathology. These findings further suggest that TREM2 may represent as a potential therapeutic target for tau-related neurodegenerative diseases.

Introduction

Tau pathology, usually refers to the intraneuronal hyperphosphorylation of tau protein, is considered as a pathological hallmark for a variety of neurodegenerative diseases, especially Alzheimer's disease (AD) and frontotemporal dementia (FTD) (Ballatore et al., 2007, Hanger et al., 2014). In the brain of AD and FTD animal models, tau hyperphosphorylation disrupts the stability of the cellular cytoskeleton, subsequently leading to dysfunction or even damage of neurons and synapses (Honson and Kuret, 2008). More importantly, compelling evidence indicates that tau pathology is closely associated with the severity of cognitive deficits in patients with AD or FTD (Giannakopoulos et al., 2003, Xu et al., 2014). In view of its critical role in the pathogenesis of these 2 diseases, more needs to be done to elucidate potential mechanisms affecting the formation and progression of tau pathology.

Recent genetic studies suggest that triggering receptor expressed on myeloid cells 2 (TREM2) gene may be associated with the susceptibility of AD because a low-frequency variant R47H increases the risk of this disease by nearly 3-fold in Caucasian populations (Guerreiro et al., 2013a, Jonsson et al., 2013). Interestingly, loss-of-function mutations in TREM2 gene are also related with the clinical phenotypes and neuropathology of FTD, supporting the contribution of TREM2 to the pathogenesis and progression of this disorder (Guerreiro et al., 2013b, Rayaprolu et al., 2013). TREM2 is a 230 amino acid type I transmembrane receptor that belongs to the superfamily of immunoglobulin (Colonna, 2003). As its name implies, TREM2 is expressed by a subset of myeloid cells including monocyte, dendritic cells, osteoclasts, and tissue macrophages in blood and peripheral tissues (Hu et al., 2014, Jiang et al., 2013). In the brain, we and others showed that TREM2 was uniquely expressed by microglia, the main immune cell within central nervous system, and coupled with DAP12 for its signaling (Ma et al., 2015, Takahashi et al., 2005, Takahashi et al., 2007, Ulrich et al., 2014). More importantly, several lines of evidence suggest an essential role of TREM2 in modulation of microglial functions, especially the phagocytosis and the proinflammatory reactions (Kleinberger et al., 2014, Melchior et al., 2010, Takahashi et al., 2005, Takahashi et al., 2007).

Coincidentally, 3 recent studies have proposed a potential association between TREM2 protein and tau pathology in AD, the most common type of tau-related neurodegenerative disorder. Cruchaga et al. (2013) showed that TREM2 R47H variant was related to higher levels of total tau and hyperphosphorylated tau protein in the cerebral spinal fluid of AD patients. Meanwhile, this finding has been further confirmed by Lill et al. (2015) in a larger cohort of AD patients. Furthermore, Lue et al. (2015) found that TREM2 expression was positively correlated with phosphorylated tau protein in postmortem brain samples from patients with AD. Despite these clinical findings, the precise role of TREM2 in the formation and progression of tau pathology remains largely unknown.

In this study, using P301S mice, a transgenic animal model of tau pathology, we showed that TREM2 was upregulated in microglia during disease progression. Silencing of brain TREM2 using a lentiviral-mediated strategy exacerbated tau pathology in P301S mice. This exacerbation of tau pathology might be attributed to neuroinflammation-induced hyperactivation of tau kinases. Additionally, more severe neurodegenerative changes and spatial learning deficits were observed after TREM2 silencing. Taken together, our results imply that TREM2 attenuates the activity of tau kinases through restriction of neuroinflammation, and thus plays a protective role against tau pathology. These findings further indicate that TREM2 may represent as a potential therapeutic target for tau-related neurodegenerative diseases, such as AD and FTD.